Syncope is a temporary loss of consciousness usually related to insufficient blood flow to the brain. It's also called fainting or "passing out.” Syncope is responsible for 3% to 5% of emergency department visits, with a hospitalization rate in about 40% of cases, with an average stay of 5.5 days. The Canadian Syncope Risk Score showed good discrimination and calibration for 30-day risk of serious adverse events after disposition from the emergency department.The aim was to assess Canadian Syncope Risk Score in predicting outcomes and mortality at the emergency department of Suez Canal University Hospitals.A prospective observational cohort study was carried out in emergency department in Suez Canal University Hospital. After approval by the Ethical and Research Committee of Faculty of Medicine, Suez Canal University, 60 patients with syncope attending to emergency department were included to this study. All included participants were assessed by history taking and they also assessed by the Canadian Syncope Risk Score.P-value <.001. At a cut-off point of more than 3 for the Canadian Syncope Risk Score's, sensitivity of that score in complication's occurrence prediction was 100% and the specificity was 87.5% P-value <.001.The Canadian Syncope Risk Score's mean of the study group was 4.9 and the range of the scores was from −2 to 11. The mean of the percentage of risk of serious events at 30 days in the study group was 29.17% and it ranged from 0.7% to 83.6%.There was a statistically significant difference between means Canadian Syncope Risk Score's score regarding complication occurrence. Cases which showed complications had a mean score of 7.33 compared to a mean score of 1.25 in case of no complication occurrence The Canadian Syncope Risk Score's is strong predictor for risk of serious adverse events and a good indicator for admission, with 100% sensitivity and 87.5% specificity at cut off point more than 3. It's also called fainting or “passing out.” Syncope is a common medical problem, with a frequency between 15% and 39%. In the general population, the annual number episodes are 18.1 to 39.7 per 1000 patients, with similar incidence between genders. This framework is secondary to cerebral hypoperfusion, with short duration (average 12 seconds). The first report of the incidence of syncope is 6.2 per 1000 person-years. However, there is a significant increase in the incidence of syncope after 70 years of age, with 5.7 episodes/1000 individuals per year between 60 and 69 years old and with 11.1 episodes/1000 individuals per year between 70- and 79-years age. After 80 years, the annual incidence may reach 19.5 per 1000 individuals.In the general population, the annual number episodes are 18.1 to 39.7 per 1000 patients, with similar incidence between genders, and with high prevalence between 10 and 30 years of age, mainly of vasovagal syncope.The most commonly considered 7-day outcomes are mortality, dysrhythmias, myocardial infarction, stroke, and rehospitalization. The most commonly considered 30-day outcomes are mortality, hemorrhage requiring blood transfusion, dysrhythmias, myocardial infarction, pacemaker or implantable defibrillator implantation, stroke, pulmonary embolism, and syncope relapse.Thiruganasambandamoorthy et al, prospectively enrolled adults (age ≥ 16 years) with syncope who presented within 24 hours after the event to 1 of 6 large emergency departments from September 29, 2010 to February 27, 2014. then collected standardized variables at index presentation from clinical evaluation and investigations. Adjudicated serious adverse events included death, myocardial infarction, arrhythmia, structural heart disease, pulmonary embolism, serious hemorrhage and procedural interventions within 30 days.Thiruganasambandamoorthy et al, reported that the Canadian Syncope Risk Score showed good discrimination and calibration for 30-day risk of serious adverse events after disposition from the emergency department. Once validated, the tool will be able to accurately stratify the risk of serious adverse events among patients presenting with syncope, including those at low risk who can be discharged home quickly.The Canadian Syncope Risk Score (CSRS) is the latest syncope decision rule to be developed; nine predictors were derived, encompassing clinical evaluation, investigations and likely ED diagnosis to produce a patient risk score between −3 and 11. Risk scores are grouped into risk categories based on the likelihood of serious adverse events (SAEs).1.1Our study aimed to determine the ability of the CSRS to predict 30-day serious outcomes in patients presenting to the emergency department of Suez Canal university teaching hospitals (ED) with syncope.2A prospective observational cohort study was carried out in emergency department in Suez Canal University Hospital. After approval by the Ethical and Research Committee of Faculty of Medicine, Suez Canal University(reference: research #4290) (chairman of the committee:professor dr. Amani Waheed), 60 patients with syncope attending to emergency department were included to this study.:The sample size was calculated using the following formula Sn = Sensitivity = 97.8%, and E = Margin of error/width of confidence interval = 5.5%.where n = sample size, Zα/2 = 1.96 , P = Prevalence/proportion of disease = 16.8%,So, by calculation, the sample size is equal to 60 subjects after addition of 10% drop-out proportion.All included participants were assessed by history taking and they also assessed by the Canadian Syncope Risk Score. Patients were followed up by phone at 30 days after their index presentation to determine the occurrence of SAE. A 30-day SAE was recorded if any of the following occurred during follow up: death, arrhythmia, myocardial infarction, serious structural heart disease, aortic dissection, pulmonary embolism, severe pulmonary artery hypertension, subarachnoid hemorrhage, significant hemorrhage, any other serious condition or procedural intervention used to treat syncope. Patients unable to be contacted were considered lost to follow up and local heath databases and death registry checked. Patients were followed up by phone and when they returned back to outpatient clinic to assess their conditions.2.1We followed up the patients over one month duration from entering the emergency department with syncope. First we contacted the patients by phone and they were assessed by coming to regular visits to the outpatient clinic during the 30 days.2.2P < .05 was considered significant.Statistical analyses were performed using Statistical Package for the Social Sciences for Windows version 22. The numerical variables was expressed in terms of mean and standard deviation (Mean ± SD), and qualitative variables were expressed in terms of frequency and frequency percentage. The normality of variables was tested with the Kolmogorov–Smirnov test. Chi-squared test was used for categorical data. Results were expressed as mean ± SD or n, % and 3The present study showed that age's mean is (55.9 ± 8.30) years old, males represented 51.7% as shown in Table The CSRS's mean of the study group was 4.9 and the range of the scores was from −2 to 11. And very high-risk cases had the highest distribution (35%), while cases with very low risk had lowest distribution (10%).Risk of serious adverse event score regarding complication occurrence. With higher scores in Cases which showed complication.The most frequent complication which occurred within 30 days in this study was uncontrolled atrial fibrillation, followed by myocardial infarction and Supraventricular tachycardia and the least frequent were gastrointestinal bleeding and pulmonary embolism; there was a statistically significant difference between means Also, we found 46.7% of cases was admitted, and those who were admitted, had mean CSRS score significantly higher than cases of on-site patient discharge, and Cases which showed complications had a significantly higher CSRS score than in case of no complication occurrence.At cut-off point of more than 3 for the CSRS, sensitivity of that score in complication's occurrence prediction was 100% and the specificity was 87.5% meaning that the score is better in ruling out the complications’ occurrence. The receiver operating characteristic (ROC) curve showed a significant area under curve (AUC) of 0.974 as shown in Table 4The CSRS was developed to predict 30-day serious outcomes; it consists of three parameters; (1) Clinical evaluation ”Predisposition to vasovagal symptoms, history of heart disease and Any systolic pressure reading <90 or >180 mm Hg” (2); Investigations; “Elevated troponin level , abnormal QRS axis (<–30° or >100°), QRS duration >130 ms, and Corrected QT interval >480 ms” and (3); Diagnosis in emergency department; Vasovagal syncope or Cardiac syncope, its score ranged between (−3 to 11) for interpretation A score of −2 or lower confers a very low risk (<1%), scores of −1 to 3 confer a low to medium risk (1%–8%), and scores of 4 or more confer a high or very high risk (>12%).Our study aimed to determine the ability of the CSRS to predict 30-day serious outcomes in patients presenting to the emergency department of Suez Canal university teaching hospitals (ED) with syncope.4.1 and Thiruganasambandamoorthy et al, 2016 study that enrolled 4030 patients at 6 large emergency departments in teaching hospitals in 4 Canadian cities, regarding age but differ with them as they found female represent higher prevalence.The current study enrolled 60 patients with acute syncope, it shows that the mean of age is (55.9 ± 8.30) years old as shown in Table 4.2In the current study the CSRS's mean of the study group was 4.9 and the range of the scores was from −2 to 11.Our study showed that very high-risk cases had the highest distribution (35%), while cases with very low risk had lowest distribution (10%). Our results in line with Zimmermann et al, 2020 who found The rate of observed serious outcomes within 30 days increased from 0.8% in the very low risk group  to 48% in the (very) high risk group .In other hand, there were 141 (49.8%) very-low-risk, 62 (21.9%) low-risk, 61 (21.6%) medium-risk, 12 (4.2%) high-risk and 7 (2.5%) very-high-risk patients identified in Chan et al, 2020 study.4.3We defined a serious adverse event as the detection or occurrence of any serious condition related to syncope within 30 days after disposition from the emergency department. The composite outcome included any of the following serious adverse events: death, arrhythmia, myocardial infarction, serious structural heart disease, aortic dissection, pulmonary embolism, severe pulmonary hypertension, severe hemorrhage, subarachnoid hemorrhage, any other serious condition causing syncope and procedural interventions for the treatment of syncope.The present study found the most frequent complication which occurred within 30 days in this study was uncontrolled atrial fibrillation (22.2%), followed by myocardial infarction (16.7%), supraventricular tachycardia (16.7%) and the least frequent were gastrointestinal bleeding (8.3%) and pulmonary embolism (8.3%).Ragan and Lin, 2021 study showed that; in the low-risk groups, 0.3% of very low risk and 0.7% of low-risk patients experienced any serious 30-day outcome with no ventricular arrhythmias or deaths observed. In the highest risk group, 51.3% of patients experienced any serious outcome with 7 deaths and 33 arrhythmias observed.4.4In the present study; 46.7% of cases was admitted, and those who were admitted, had mean CSRS score significantly higher than discharged cases, and cases which showed complications had a significantly higher CSRS score than in cases with no complication,11Thiruganasambandamoorthy et al, 2020 study found that the short-term serious morbidity and mortality for ED syncope was very low, with 0.3% risk for each of 30-day mortality and ventricular arrhythmia, as previously reported. Our results inconsistence with Thiruganasambandamoorthy et al, 2020 who found a statistically significant difference in between the distributions of complication occurrence regarding on-site admission of patients. Admitted cases with complications’ occurrence were 31 compared to only one case which had complications although not admitted.Additionally, none of the patients in these categories died or experienced ventricular arrhythmia. Hence, they believe that these patients can be discharged quickly after ED evaluation.The difference between these results illustrated as our population is hospital based and it is only a small fraction of patients from the general population that presents in a clinical setting.4.5For validation in the current study; we found at cut-off point of more than 3 for the CSRS, sensitivity of that score in complication's occurrence prediction was 100% and the specificity was 87.5% meaning that the score is better in ruling out the complications’ occurrence. The ROC curve showed a significant AUC of 0.974 as shown in Table The correlations between risk of serious adverse events and both CSRS and risk category were strong positive statistically significant. We agree with . In a recent metacentric study, enrolled 3819 patients they found (0.3%) patients at very low risk and (0.7%) patients at low risk experienced 30-day serious outcomes, and this proportion significantly increased to 40 of 78 (51.3%) total patients in the very-high-risk group. There were similar steady significant increases in the subtypes of serious outcomes from the very-low-risk to the very-high-risk categories.All these finding illustrated that CSRS is strong predictor for risk of serious adverse events and a good indicator for admission. .Many studies discussed the validity of CSRS as Thiruganasambandamoorthy et al, 2020 study who reported an AUC of 0.88Ragan and Lin, At a threshold score of −1, the CSRS performed with a sensitivity of 97.8% (95% CI 93.8%–99.6%) and a specificity of 44.3% (95% CI 42.7%–45.9%). The AUC of the model was 0.91 (95% CI 0.88–0.93).In other study conducted by Thiruganasambandamoorthy et al, 2018 The accuracy of the CSRS remained high with area under the ROC curve at 0.87 (95% CI 0.82–0.92), similar to the derivation phase . The score showed excellent calibration at the prespecified risk strata. For the very-low risk category (0.3% SAE of which 0.2% were arrhythmia and no deaths) the sensitivity was 97.5% and negative predictive value was 99.7% (95% CI 98.7–99.9). For the very high-risk category (61.5% SAE of which 26.9% were arrhythmia and 11.5% death) the specificity was 99.4% and positive predictive value was 61.5% (95% CI 43.0–77.2).Chan et al, 2020 mentioned that for a threshold of −1 or higher there were 137 false positive cases and for a threshold of 1 or higher there were 75. The number of false negative cases (n = 2) did not change with the different thresholds examined. The CSRS had a sensitivity of 71.4% and specificity of 50.4% for a threshold score of–1 or higher. The CSRS performed with the same sensitivity for a threshold score of 1 or higher but with higher specificity of 72.8%.4.6The low prevalence of 30-day SAEs in our study and syncope patients in general has been acknowledged previously as one of the challenges in validating any syncope clinical decision rule.5Syncope accounting for 1% to 3% of all emergency department visits.The ages mean is (55.9 ± 8.30) years old. Males represented 51.7%.Most prevalent type of syncope is cardiac syncope represent about 65%.The CSRS is strong predictor for risk of serious adverse events and a good indicator for admission, with 100% sensitivity and 87.5% specificity at cut off point more than 3, for complication's prediction, meaning that the score is better in ruling out the complications occurrence.There was a statistically significant difference between means CSRS score regarding complication occurrence. Cases which showed complications had a mean score of 7.33 compared to a mean score of 1.25 in case of no complication occurrence.6Based on the study results, we recommend that patients with very low- risk and low-risk CSRS can be discharged.Patients at medium risk be involved in a shared decision approach regarding disposition.Patients at high risk should be hospitalized for a short course.Implementation of the CSRS will improve patient safety and reduce health care resource use unnecessary investigations and unneeded hospitalization.Supervision: Ahmed Abou zeid, Bassant Mousa, Bassant Moussa, Mohamed Ali.Writing – original draft: Ahmed Abdelnasr, Ahmed Ali.Writing – review & editing: Bassant Mousa, Bassant Moussa.


At month 18, 14 (77.8%) and 11 (61.1%) eyes had an IOP ≤ 16 mmHg and ≤ 14 mmHg, respectively, without ocular hypotensive medication. The mean number of ocular hypotensive medication taken was significantly reduced from 2.3 ± 0.9 drugs at baseline to 1.0 ± 1.4 drugs at month 18 (p = 0.0020). Four (17.4%) eyes had hypotony at postoperative day 1, which was successfully resolved without sequelae. Four (17.4%) eyes underwent a needling procedure and four (17.4%) eyes underwent additional surgeries. Conclusions: The XEN63, either alone or in combination with cataract surgery, significantly lowered the IOP and reduced the need for ocular hypotensive drugs over a period of 18 months.Background: Glaucoma surgery has significantly evolved over the last years. This paper aims to evaluate the midterm clinical outcomes of the XEN63 device in a real-world scenario. Methods: A retrospective clinical study was conducted on consecutive patients who underwent an XEN63 implant insertion, either alone or in combination with phacoemulsification. The primary endpoint was the mean intraocular pressure (IOP) at the month 18 visit. Results: Twenty-three eyes (23 patients) were included in the analysis. The preoperative IOP was significantly lowered from 27.0 ± 7.8 mmHg to 14.1 ± 3.4 mmHg at month 18 ( Glaucoma surgery has experienced important advances over the last several years . Among tUnder the umbrella of the term MIGS, different devices have been included that share a series of common characteristics, such as an adequate IOP reduction with reduced tissue destruction, a good safety profile, shorter surgical time, and rapid postoperative recovery ,3,4. HowAlthough there may be certain objections when considering the XEN device as a MIGS , for theThe evidence evaluating the effectiveness of the XEN63 implant is very limited ,9,10,11,The new XEN63 device uses the same needle injector as the XEN45 for preventing early side flow and hypotony .We recently published a study, which mainly focused on the safety profile of this device in the early postoperative period (3 months) .The main purpose of the current study is to evaluate the midterm effectiveness and safety of the XEN63 device in patients with glaucoma in a real clinical setting.A retrospective, open-label, and bicenter clinical study was conducted on consecutive patients who underwent an XEN63 implant insertion, either alone or in combination with phacoemulsification.The study protocol was approved by the Ethics Committee of the University of Torino, which waived the need for written informed consent. The study was conducted in compliance with the Declaration of Helsinki principles and with Council for Harmonization Good Clinical Practice guidelines.The study was conducted on consecutive glaucoma patients who underwent an XEN63 implant insertion, either alone or in combination with cataract surgery, between February and June 2020.Patients included in the study were aged ≥ 40 years, had a clinical diagnosis of glaucoma, and an unmet target IOP despite medical therapy. Patients with narrow-angle glaucoma were included if, in the surgeon’s opinion, there was enough space to implant the device safely. Patients with closed-angle glaucoma; severe conjunctival problems; phacodonesis; progressive retinal or optic nerve disease of any cause; or history of major ocular surgery (except phacoemulsification) within the previous 6 months were excluded from the study.®63 . It is composed of porcine gelatin crosslinked with glutaraldehyde; it is 6.0 mm long with an outer diameter of 180 μm, and an inner diameter of 63 μm.The MIGS device used in this study was the XENAll the surgical procedures were performed under local anesthesia by the same two surgeons (AMF and MF) who were experienced in this type of surgery.An intra-Tenon mitomycin-C (MMC) injection (0.1 mL of MMC 0.02–0.03%) was administered into the superonasal quadrant prior to surgery.The device was placed in the superior nasal quadrant using a standard ab interno technique ,12,13. The surgical technique was meticulously detailed in a previous paper .In summary, the preloaded injector needle was inserted at the inferotemporal quadrant through a 1.8 mm corneal paracentesis. The final position of the implant was checked with gonioscopy before removing the viscoelastic material.Sideways movements of the implant were performed, until we were able to verify that the implant could move freely under the conjunctiva, to confirm the lack of adhesion.In those eyes which underwent a combined surgery (XEN + cataract), XEN63 was implanted in all cases after phacoemulsification.Perioperative care included antibiotic therapy 4 times a day during 1 week and anti-inflammatory therapy with steroids 6 times daily, which was slowly tapered over three months.IOP-lowering medications, both topical and systemic, were suspended on the day of surgery.Needling procedures were performed in the operating room in those eyes with bleb fibrosis, flat bleb, and/or elevated IOP. Needling was the first-choice treatment in these patients. The study protocol allowed up to two needling procedures per eye, after which we proceeded to either use medication and perform a revision or further surgery, as appropriate.The primary endpoint was the mean IOP at the last follow-up visit.Secondary endpoints included the mean IOP lowering from preoperative values; reduction in number of ocular hypotensive medications from baseline; proportion of eyes achieving a final IOP ≤ 12 mmHg; ≤ 14 mmHg; ≤ 16 mmHg; ≤ 18 mmHg; or ≤ 21 mmHg with and without medications; and incidence of adverse events.Success was defined as a month 18 IOP ≤ 16 mmHg without (complete success) or with  hypotensive medication and an IOP lowering from preoperative values of at least 30%.® Statistical Software version 20.104 ).A statistical analysis was performed using Prism 9 version 9.0  and MedCalcBecause a sample size calculation was not performed, we conducted a post hoc power analysis for an alpha level of 0.05; the study sample size and the effect size were observed in the study .Data were expressed as number (percentage), mean ± standard deviation (SD), or mean  as appropriate.The Shapiro–Wilks test was used for assessing the normal distribution of quantitative variables.Changes in IOP and number of ocular hypotensive medications were performed by means of repeated measures ANOVA and the Greenhouse–Geisser correction test.The last-observation-carried-forward method was used to impute missing data.Complete success survival rate was plotted using a Kaplan–Meier analysis.Data for patients who underwent an additional glaucoma surgery were censored at the time of surgery.p value of less than 0.05 was considered significant.A total of 23 eyes (23 patients) was included in the analysis, 20 (87.0%) eyes underwent XEN alone, and 3 (13.0) eyes underwent combined surgery (XEN + phacoemulsification). In the overall study sample, the mean age was 67.8 ± 15.3 years, 15 (65.2%) were women, and 14 (60.9%) had a clinical diagnosis of primary OAG. p < 0.0001)  .p < 0.0001 and p = 0.0012, respectively).Similarly, preoperative IOP was significantly reduced from 26.5 ± 8.2 mmHg and 30.3 ± 3.3 mmHg to 14.2 ± 3.7 mmHg and 13.7 ± 1.5 mmHg in the XEN alone and XEN + phacoemulsification groups, respectively  and 11 (47.8%) patients had an IOP ≤ 16 mmHg and ≤ 14 mmHg, respectively, without ocular hypotensive medication .According to the Kaplan–Meier survival analysis, complete success occurred in 60.9% of eyes .p = 0.0020; p = 0.0002; and p = 0.0027, respectively).The mean number of ocular hypotensive medications used was significantly reduced from 2.3 ± 0.9, 2.3 ± 1.0, and 2.3 ± 0.6 drugs at the preoperative visit to 1.0 ± 1.4, 0.8 ± 0.9, and 0.0 ± 0.0 drugs at month 18 in the overall, XEN solo, and XEN + phaco samples, respectively  eyes had hypotony (defined as an IOP ≤ 6 mm Hg) at postoperative day 1, which was successfully resolved without sequelae. One (4.3%) eye had anterior chamber bleeding during the surgery, one (4.3%) eye had a 1.5 mm hyphema at postoperative day 1, and four (17.4%) had choroidal detachment (three at postoperative day 7 and one at postoperative day 15), which was successfully resolved with medical treatment, at month 1 visit.Four (17.4%) eyes underwent a needling procedure (mean time for needling 42.9 ± 11.2 days), although only one eye did so due to an elevated IOP.Four eyes underwent additional surgeries, two (8.7%) eyes underwent trabeculectomy, one (4.3%) eye underwent a device replacement (a new XEN45 device was implanted), and one eye (4.3%) underwent a high-intensity focused ultrasound cyclodestruction (HIFU) procedure . HoweverThe BCVA did not change over the course of the study (mean change: 0.1 ± 0.2).At month 18, one (5.6%) eye showed a ≥ 2-line worsening in BCVA as compared to baseline, while five (27.8%) eyes showed a ≥ 2-line improvement as compared to baseline .Although glaucoma treatment must follow a patient-tailored approach, in most cases, medical treatment represents the first therapeutic step . HoweverCurrent scientific evidence with the XEN63 device is very limited ,9,10,11 The main difference between the current XEN63 device and the former one is the surgical technique. The new XEN63 device uses a 27G injector, which has the advantage of minimizing the side flow, and, in addition, it is inserted in the anterior chamber through a 1.8 mm corneal paracentesis (the former one used a 25G injector that required a 2.2 mm paracentesis). On the other hand, the studies evaluating the former XEN63 device were performed without MMC ,10.The results of the studies evaluating the former XEN63 device have pointed in the same direction, indicating its good efficacy and safety profile ,8,9,10. According to the results of our study, the XEN63 device significantly lowered the IOP and reduced the number of ocular hypotensive medications during a follow-up period of 18 months.In addition, the rate of adverse events was relatively low; the majority of them were mild in severity and were resolved without sequelae (with or without medication).As far as we know, this is the first paper evaluating the midterm effectiveness and safety of the new XEN63 device.In a previous paper published by our group, the short-term (3 months) efficacy and safety profiles of this device were analyzed . The resUp to now, only XEN45 has been available on the market. The available scientific evidence has shown the mid- and long-term good efficacy and safety profile of this device. When comparing the results of the current study to those of the XEN45 device, it can be observed that the IOP lowering achieved with XEN63 was consistently greater see . MoreoveIn the current study, four (21.7%) eyes required additional surgery . These eyes were those with the highest preoperative IOP , which could indicate the need for more aggressive procedures for treating these patients.Regarding safety, the most commonly reported adverse event was choroidal detachment (four eyes), which was successfully resolved without treatment at the month 1 visit.Hypotony, defined as an IOP < 6 mmHg, was observed in four (17.4%) eyes at postoperative day 1. In all cases, it was resolved without consequences. The incidence of hypotony reported in studies performed with the former device was similar to ours ,10, althIn our study, postoperative hypotony was not related to ocular complications or visual acuity loss. In the eyes which underwent the XEN63 implant alone, four eyes experienced visual acuity worsening ≥ 1 line, whilenine9 eyes experienced visual acuity improvement ≥ 1 line.Glaucomatous damage is defined by retinal ganglion cell loss and their axons, although the exact mechanism of retinal ganglion cell death has not been fully elucidated. Once apoptosis has occurred, it is difficult to conceive how visual function might improve. However, before retinal ganglion cell death occurs, they might undergo a period of reversible dysfunction . This hyWith regard to visual acuity worsening, Lenzhofer et al.  reportedRegarding needling, in the current study, four (17.4%) eyes underwent postoperative needling, which was a lower rate compared to the one reported in previous XEN45 papers ,27,28,30When interpreting the results of this study, it is necessary to take into account several limitations. The main one was its retrospective design. Retrospective studies are associated with bias and confounding factors, although the inclusion/exclusion criteria used in our study might limit their impact. The second limitation was the small sample size. Although the sample size was not calculated prior to the study, the power for detecting the observed differences in IOP and the number of ocular hypotensive medications, between preoperative and month 18 values, was 99% and 96%, respectively. Additionally, only three eyes underwent combined surgery (XEN63 + phacoemulsification), which limited the interpretation of the results. Finally, the lack of a control group and its open label design were limitations to consider.According to the results of the current study, XEN63 significantly lowered the IOP and reduced the need for ocular hypotensive drugs over a period of 18 months. Additionally, the low rate of complications (the majority of them mild in severity) makes this procedure a safe option.Different issues, including the impact of the MMC dose on the outcomes, potential factors associated with the procedure success, or whether it may be considered a cost-effective procedure, deserve larger and more controlled trials.


Background: The objectives of this study were: 1) estimate the impact and severity of both diagnosed and undiagnosed depression in the general US population 2) explore the demographics of depression based on its common symptoms 3) interpret Patient Health Questionnaire-9 (PHQ-9) scores to improve accuracy in identifying individuals with depression.Methods: A random sample of 200 individuals was selected from a general US adult population to complete the Patient Health Questionnaire-9 (PHQ-9).Results: Only 39.4% of respondents indicated that they had a formal diagnosis of depression. In contrast, 53% of participants have considered seeking help from a mental health professional. More importantly, 31.45% of respondents without a formal diagnosis had a PHQ-9 score of over 10 (moderate to severe depression).Conclusions: The results indicate that undiagnosed depression exists in the US population and suggest that access to mental health services needs to expand across the nation. Clinical depression is a mood disorder that causes a persistent feeling of sadness and loss of interest that can affect ones thinking and behavior. This condition can lead to a variety of physical and emotional problems and often requires long-term treatment . In a noThe Patient Health Questionnaire-9 (PHQ-9) is a self-administered questionnaire designed to screen, diagnose, and monitor the severity of depression. This assessment was derived from the original PHQ which aimed to address multiple health concerns including depression, panic, anxiety, etc. The PHQ-9 was developed by Spitzer, Williams, and Kroenke under a grant from Pfizer. This self-administered nine-question questionnaire assesses each criterion of depression in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and is commonly administered at therapists’ or doctors’ offices to monitor and evaluates a patient’s mental health [The objectives of this study were: 1) estimate the impact and severity of both diagnosed and undiagnosed depression in the general US population; 2) explore the demographics of depression based on its common symptoms; 3) interpret PHQ-9 scores to improve accuracy in identifying individuals with depression.DesignA cross-sectional study was conducted in July of 2022. Data were collected through an anonymous questionnaire using an online survey platform. A convenience sample of 200 respondents included all adults in the general US population regardless of age, sex, race, or ethnicity. This study was given an exempt determination by our institutional review board (2022-578).Data collectionThe survey consisted of three parts: First, it inquired about participants' demographics including their age, gender, level of education, and income. Then the PHQ-9 assessment with a few follow-up questions regarding their diagnosis of Depression. For each of the nine questions on the Patient Health Questionnaire, the respondent was asked: “Over the last 2 weeks, how often have you been bothered by the following problems?” Each question had only four choices including “Not at all” (0 points), “Several days” (1 point), “More than half the days” (2 points), or “Nearly every day” (3 points). The scores from all nine questions were added together to compute a total score. The interpretation of the depression severity is as follows: 0-4 points indicates none-minimal depression, 5-9 indicates mild depression, 10-14 indicates moderate depression, 15-19 indicates moderate-severe depression and 20-27 indicates severe depression. A few follow-up questions were asked regarding whether the patient had been formally diagnosed with depression, thought of seeing a mental health professional, what prevents them from seeing a mental health professional, and a final open-response question allowing them to express any concerns about their depression that hadn’t previously been expressed.Statistical analysisStatistical analysis was performed using JMP version 16 . Parametric tests were used for normally distributed variables and non-parametric tests were used for skewed data. Chi-square testing was performed to assess correlation between a high PHQ-9 score and having a formal diagnosis of depression. A p-value of <0.05 was considered statistically significant.The cohort comprised of 200 individuals with 57.7% females and 42.3% males. The age distribution was 14% between the ages of 18-24, 29% between the ages of 25-24, 32% between 35-44, 10% between 45-54, and 13% of adults over the ages of 54 years old. The median age was 38, with an interquartile range of 30 to 44, and a range from 18-77 years. 31% of respondents’ highest level of education was high school, 28% university, 23% postgraduate, 15% vocational technical college, and 2% middle school. The distribution of race in the US population was: 60% White, 17% Latino, 12% Black, 6% Asian, 3% multiracial, 1% Native American and 1% other. Race was approximately proportional to the US population with 63% of respondents indicating they were White, 12% Black, 9% Hispanic, 7% Asian, 3% multiracial, with 2% preferring not to say and 4% composed of various other ethnicities. The distribution of annual household income was <$25,00 (21%), $25,000-50,000 (21%), $50,000-75,000 (16%), and $75,000-100,000 (15%), and >$100,00 (27%). In terms of marital status, 33% of participants were single, 39% were married, and 16% were living with a partner. Forty-two percent of respondents had no children, 17% had one child, 20% had two children, 12% had three children, and 4% had four children.How often do you experience little interest or pleasure in socializing?Only 22.3% indicated that they never experience little interest or pleasure in socializing. 38.3% indicated that they experience this several days, 24.4% indicated more than half the days, and 14.9% every day.How often do you feel down, depressed, or hopeless?Only 27.9% indicated that they never feel down, depressed, or hopeless, a majority of 45.3% of respondents on several days, 18.9% on more than half of the days, and 8% feeling this nearly every day.How often do you have trouble falling asleep, staying asleep, or sleeping?This question had a relatively even distribution with 37.8% of respondents saying they have trouble falling asleep on several days, 20.4% saying not at all, 20.9% indicating more than half the days, and 20.9% indicating nearly every day.How often do you feel tired or have little energy?A majority of 47.3% felt tired/had little energy on several occasions, with 12.4% never/rarely feeling tired, 17.9% more than half of the days and 22.4% nearly every day.How often do you have a poor appetite or overeating?Most participants did not seem to have any severe appetite issues with 31.8% indicating no issues, 41.3% indicating some days, 15.4% saying more than half the days and 11.4% indicating nearly every day.How often do you feel bad about yourself - or that you’re a failure or have let yourself or your family down?31.8% of participants indicated that they never/rarely feel bad about themselves or a failure to their daily. 41.3% indicated that they feel this on several days, 15.4% on more than half of the days, and 11.4% nearly every day.How often do you have trouble concentrating on things, such as reading?37.3% of respondents indicated that they do not have trouble concentrating on tasks such as reading, 39.8% indicating several days, 14.4% on more than half of the days, and 8.4% nearly every day.How often do you speak so slowly that other people could have noticed. Or the opposite - being so fidgety or restless that you have been moving around a lot more than usual?55.2% of participants indicated that they do not move too slowly or restlessly. 24.9% indicated these actions on several days, 10.9% indicating more than half the days, and 9% indicating nearly every day.How often do you have thoughts that you would be better off dead or of hurting yourself in some way?Of the most severe question asked in the survey, a majority of 65.7% indicated no thoughts of being better off dead or hurting themselves, however 22.4% indicated that they have had these thoughts on several days, 8% on more than half of the days, and a dangerous 4% on nearly every day. This marks the final question of the PHQ-9 Survey.Additional questionsInterestingly, only 39.4% of respondents have indicated that they have had a formal diagnosis of depression and 60.6% have not. In contrast, 53% of participants have considered seeking help from a mental health professional while 47% have not considered such a course of action. To account for this disparity, a follow-up question asked: “Has anything prevented you from seeking help from a mental health professional?” with the answer choices ranging from “I don’t need it”, “Too busy”, and “Can’t afford it” to “Afraid of stigma”, “Other”, or “None of the above”. The largest proportion of respondents claimed that they did not need it (32.1%) and the second highest proportion chose “None of the above” (23.9%). The final open-ended question had a wide range of responses. Some examples include: “I have been feeling very down and just tired all the time I can get more irritated very easily and I get frustrated I get annoyed easily to where I don’t want to deal with no one”, “I’ve been denied for social security 3 times already”. Notably, many responses called for the need to expand access to mental healthcare and drive down these costs. Some examples include: “Wish there were more access to free mental healthcare”, and “Mental health care should be more accessible in the USA”.PHQ-9 scoresThe distribution of PHQ-9 Scores was skewed with a mean score of 9.74 points. The minimum score reported was 0, with the 25th percentile being 5, the median was 9, the 75th percentile was 13.5, and the maximum score was 26.A statistical model was created to see whether the PHQ-9 score, age, or gender had an impact or not on whether the respondent had previously been diagnosed with depression. A high PHQ-9 score was significantly associated with a prior diagnosis of depression (P=0.0004). Age, gender, and race were not significant predictors. The adjusted R-Squared value is 0.184, meaning that 18.4% of the variation in a patient’s diagnoses can be explained by the model, indicating a solid statistical model. A separate column was generated analyzing those who had a PHQ-9 score of 10 or greater (moderate-severe depression). Almost half of the cohort (46.8%) screened positive. They were significantly more likely to have a formal diagnosis of depression when compared to those with lower scores (P<0.0001). More concerning was the 31.5% who did not have a formal diagnosis of depression but did have PHQ-9 scores >10  . DepressLimitationsSome racial/ethnic groups such as Hispanics were not as well represented as they should have been. A majority of participants were in the two lower income brackets , with less participation from the middle and upper classes. Additionally, only adults over the age of 18 were surveyed, so the prevalence of undiagnosed depression in teenagers could not be measured. One other factor to note is that many individuals suffering from depression may have declined to respond meaningfully to the survey due to personal issues. One major limitation is much of the survey was multiple choice with only four answer choices. As a result, some respondents may have had to underestimate or overestimate their responses to choose an answer. In the future, more in-depth assessments and surveys within specific demographic groups, such as lesbian, gay, bisexual, transgender, queer and intersex (LGBTQI) may facilitate more targeted and effective treatment.Our data suggests depression is ongoing, and under-diagnosed. Increasing access to affordable care may be beneficial in diagnosis, treatment, and prevention. Overall, depression continues to be an ongoing problem in America and across the globe, and healthcare access and innovative solutions are imperative for improving our nation’s mental health and quality of life.


FDC BIS + ASA was associated with excellent adherence and improved BP control. The majority (78.7%) of patients preferred the FDC.This study assessed blood pressure (BP) control and adherence in patients given a fixed-dose combination (FDC) of bisoprolol (BIS) + aspirin (ASA) compared to those given these two drugs as separate tablets. Patients with hypertension and/or coronary heart disease treated with two-pill BIS (5–10 mg) and ASA (75–100 mg) were switched to FDC BIS + ASA (either 5/75 mg or 10/75 mg) ≥4 weeks prior to study initiation. Adherence was estimated from pill counts and patients’ diaries (1–2 months and 3 months after inclusion) and using Morisky’s Medication Adherence Scale (MMAS) at 3 months. BP control with the two treatments was compared. A total of 356 patients were enrolled (mean (SD) age: 64.3 ± 11.9 years, 56.5% male). Mean (SD) duration of prior treatment with two-pill BIS and ASA was 17.8 ± 26.6 months. FDC adherence was excellent or good (≥76%) in 98.3% and 98.0% of patients based on pill counts and patients’ diaries, respectively. Overall MMAS score was 3.1 ± 1.0. A significant decrease was observed in mean systolic BP, mean diastolic BP and heart rate over the 3-month period (all  Hypertension, a major modifiable cardiovascular risk factor, is highly prevalent, with the number of hypertensive patients doubling across the world over the last two decades . In 2015Data from randomised clinical trials have shown that a reduction of SBP by 5 mmHg with pharmacological treatments reduces the risk of major cardiovascular events by about 10%. This has also been observed in subjects with a history of cardiovascular disease, and even in those with normal or high-normal blood pressure (BP) values, showing that pharmacological lowering of BP is equally effective for the primary and secondary prevention of major cardiovascular disease . CurrentIn the recent European guidelines , beta-blAntiplatelet therapy with aspirin (ASA) is also recommended as secondary prevention in some hypertensive patients, particularly those with previous cardiovascular events and a high cardiovascular risk, providing that BP is well controlled . A largeHypertension is an established risk factor for ischemic heart disease, and patients 30 years of age or older with baseline hypertension had a 63.3% lifetime risk of developing cardiovascular disease compared to a 46.1% risk for those with normal baseline BP .Combining antihypertensive drugs has been shown to result in a greater reduction in BP compared to the use of a single agent administered as monotherapy ,8. As adAn FDC of BIS + ASA has been shown to be bioequivalent to BIS and ASA given concomitantly as two separate drugs . HoweverThis open-label, non-randomised, uncontrolled, multicentre, phase IV study was conducted in subjects with essential hypertension and/or ischemic heart disease (IHD) in 17 centres in Poland between January 2015 and August 2016.The study was approved by an independent ethics committee and was performed in adherence with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use—Good Clinical Practice , the Declaration of Helsinki, 1964 and all applicable amendments. All subjects gave their written informed consent before taking part and no subject received remuneration for taking part in the study.The study is registered as: EMR200583_500.Patients with essential hypertension and/or IHD who had been receiving a free combination of BIS and ASA and were switched to an FDC of BIS + ASA at least 4 weeks prior to recruitment were included in the study.The following were the inclusion criteria: age > 18 years; essential hypertension and/or IHD; previous treatment with a free combination of BIS (5–10 mg) and ASA (75–100 mg); switched from the free combination of BIS and ASA to the FDC at least 4 weeks prior to recruitment; and reliable contraception in women of childbearing age. Exclusion criteria included: pregnancy or breast feeding; participation in another trial within 30 days prior to recruitment; any contraindication to FDC according to the summary of product characteristics; and any significant disease excluding the patient from the study.The intervention consisted of capsules containing an FDC of BIS + ASA, either 5/75 mg or 10/75 mg, one capsule to be taken daily during the 3-month study period.The trial protocol consisted of two mandatory visits, one at the start of the observation period and the other at the end of the observation period, after 3 months. An additional visit was recommended 1–2 months after enrolment to carry out an interim assessment of adherence. Demographic data, medical history, laboratory data and concomitant medications were recorded at inclusion, data regarding patient adherence, including tablet/package counts, refill rates and patient diary recordings, were collected at the interim 1–2-month visit, and data regarding patient adherence, including tablet/package counts and patient diary recordings, were recorded at the 3-month visit  and compared with adherence under the free combination. Adherence was also assessed at the 3-month visit using the self-reported four-item Morisky Green Levine Medication Adherence scale (MMAS) . The resThe data collected at the different visits are summarised in The primary outcome measure was the percentage of patients with good or excellent adherence during the 3 months of FDC treatment, assessed from the patients’ diaries and tablet/package counts. Excellent adherence was defined as intake of >90% of prescribed capsules, good adherence as intake of 76–90% of prescribed capsules, moderate adherence as intake of 51–75% of prescribed capsules and poor adherence as intake of ≤50% of prescribed capsules. Overall adherence was calculated by combining the excellent and good categories.The secondary endpoints were the frequency and severity of adverse events (AEs) and the patients’ preference (free vs. FDC vs. no preference). AEs were summarised as number and percentage by Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and preferred term within SOC for causality, severity and seriousness.The number of study participants was calculated as at least 200, assuming 90% of subjects with excellent or good adherence, level of significance 5%, precision 5% and a dropout rate of 30%. Depending on at least 200 subjects, a 95% confidence interval [95%CI] was calculated for 90% of subjects with assumed excellent or good adherence.n), number of subjects with missing values (missing data), mean, standard deviation (SD), median, lower quartile (Q1), upper quartile (Q3) and range (min–max). Categorical variables are reported as frequency (n) and percentage, and 95%CI, including missing observations. The R Stats Package was used for calculations.Continuous variables are reported as number of subjects  included all subjects enrolled in the study (who gave their informed consent and received at least one dose of study treatment). The safety population included all subjects enrolled in the study who received at least one dose of study treatment.A total of 408 subjects were screened, 356 were enrolled (FAS) and 350 (98.3%) completed the study. Among the six subjects (1.7%) who were withdrawn from the study the most common reason for withdrawal was “did not attend the final visit” (0.6%). A flow chart of the study population is shown in 2 (range: 18–49 kg/m2)  were male and 155 (43.5%) were female. Mean (± SD) age was 64.3 ± 11.9 years (range: 26–87 years) and mean (± SD) body mass index (BMI) was 28.7 ± 4.05 kg/m9 kg/m2) . Forty-oHypertension was diagnosed in 339 (95.2%) patients and IHD in 234 (65.7%). Mean (± SD) duration of hypertension was 9.15 ± 6.56 years (range: 0.1–43.8) and mean duration of IHD was 6.65 ± 5.88 years (range: 0.1–35.8). Mean (± SD) duration of free dose combination BIS and ASA (months) prior to the study was 17.8 ± 26.6 months (range: 1–187 months) . Mean (±p < 0.001), mean diastolic BP (DBP) decreased from 78.1 ± 9.0 mmHg to 76.0 ± 8.3 mmHg (p < 0.001) and heart rate decreased from 68.7 ± 6.9 beats/min to 66.0 ± 6.8 beats/min (p < 0.001).During the study period, mean (± SD) systolic BP (SBP) decreased from 130.9 ± 11.8 mmHg to 126.6 ± 11.7 mmHg , excellent adherence (>90%) was observed in 331 patients (93.0%) and good adherence (76–90%) in 19 (5.3%). Excellent + good adherence (≥76%) was observed in 350 subjects (98.3%) . Data weA similar trend in adherence was observed at the interim visit .At the EOS (3 months), 323 patients (90.7%) reported excellent adherence, 26 (7.3%) reported good adherence and one (0.3%) reported moderate (51–75%) adherence. Excellent + good (≥76%) adherence was observed in 349 subjects (98.0%). Data were missing for six patients.A similar trend in adherence was observed at the interim visit .MMAS score at EOS was 0 in three patients (0.8%), 1 in 25 subjects (7.0%), 2 in 63 subjects (17.7%), 3 in 89 subjects (25.0%) and 4 in 170 subjects (47.8%). Data were missing for six subjects (1.7%). Mean (SD) overall MMAS score at EOS was 3.1 ± 1.01 .Adherence measured with various methods (diaries and MMAS) was not different in subjects with IHD or hypertension only as compared to patients with IHD and hypertension. Drinking and smoking status were not associated with differences in rates of adherence.n = 1, 0.3%), gastro-oesophageal reflux disease , influenza , viral upper respiratory tract infection  and back pain . All AEs were mild in nature and none required withdrawal of therapy or down-titration of the BIS dose. No serious AEs were reported.Of the 356 subjects, six reported an AE during the study. The AEs reported were bradycardia (The majority of the patients (78.7%) stated that they preferred the FDC, while 10.4% said they had no preference . MedicatThe data for vital signs and number of angina attacks are summarised in This open-label, non-randomised, uncontrolled study assessed adherence and preference for FDC BIS + ASA in patients with essential hypertension and/or IHD who had previously been given a combination of BIS and ASA as a two-pill regime. At the end of the 3-month study period, excellent or good adherence (≥76%) was observed in 98.3% [95%CI: 96.4–99.4] of patients from pill counts and in 98.0% using data from the patients’ diaries. Furthermore, the majority of patients (78.7%) preferred the FDC to the two-pill combination of BIS and ASA. Medication persistence was 98.3% and tolerance of FDC was excellent with only two mild treatment-related AEs reported (0.6%).A number of randomised, controlled trials have shown that the administration of BP-lowering drugs to patients with hypertension reduces the risk of major clinical cardiovascular events  . BIS  adherence with FDC BIS + ASA and better control of BP compared to the two-pill approach. Furthermore, the majority of patients preferred to take one pill rather than undergo a two-pill regime. Tolerance of the FDC was excellent with only two mild drug-related AEs reported (0.6%).This was a prospective, observational study with no parallel control group. It is well-known that appropriate selection of patients and active surveillance during a trial may increase both patient compliance and adherence. In addition, patients were observed for a short period (3 months), whereas persistence with therapy seems to gradually decrease gradually over time. We estimated adherence based on subjective data provided by the patients themselves. We did not use the most objective method of chemical adherence testing which is recommended in patients with suspected resistant hypertension .The percentage of subjects with excellent to good adherence during 3 months of treatment with FDC BIS + ASA was 98.3%. The majority of subjects preferred the FDC to the free combination of BIS and ASA. The FDC was well tolerated with only two treatment-related AEs (0.6%) reported. This combination should be considered as preventative therapy in patients with hypertension and IHD to increase adherence.


This cross-sectional study compares trends in the prevalence of binge drinking and heavy alcohol consumption among pregnant and nonpregnant women from 2011 through 2020. Recent data on binge drinking among pregnant women suggests a modest increase from 2011 to 20183 and no increase from 2018 to 2020.4 However, little is known about how longer trends in problematic alcohol use may differ between pregnant and nonpregnant women. We sought to compare trends in prevalence of binge drinking and heavy alcohol consumption among pregnant and nonpregnant women from 2011 through 2020.Alcohol-related mortality has been increasing among women in the US during the past 2 decades.STROBE reporting guideline.This cross-sectional study obtained public use data from the Behavioral Risk Factor Surveillance System (BRFSS) from January 1, 2011, to December 31, 2020. The BRFSS is a nationally representative, cross-sectional sample of US adults that measures alcohol consumption based on 30-day recall. The BRFSS defines binge drinking as 4 or more drinks during a single occasion and heavy alcohol consumption as 8 or more drinks per week .Age- and race and ethnicity–adjusted prevalence of binge drinking and heavy alcohol consumption were estimated using logistic regression models adjusted for complex survey design and weighting. Log linear regression models were used to estimate average annual percentage change (AAPC) in prevalence rates with 95% CIs. Two-sided P < .001). Pregnant women were less likely to be non-Hispanic White (50.5%) compared with nonpregnant women (54.4%) (P < .001) (P = .003) (P = .28), reflecting an increase from 2012 to 2019. Prevalence of heavy alcohol consumption increased from 0.7%  in 2011 to 3.2%  in 2020 for pregnant women, an AAPC of 11.6% . Prevalence of heavy alcohol consumption for nonpregnant women increased from 6.6%  in 2011 to 7.5%  in 2020, an AAPC of 2.3% .Among the 49 098 pregnant women included in the study, 28.8% were 18 to 24 years of age and 3.7% were 40 to 44 years of age compared with 26.2% and 19.1%, respectively, for the 1 243 402 nonpregnant women ( < .001) . The pre = .003) . Binge dIn this cross-sectional study, we found that binge drinking and heavy alcohol consumption were higher among nonpregnant women than pregnant women, but the AAPC for both behaviors was significantly greater among pregnant women than nonpregnant women. Binge drinking increased by 0.7% per year between 2012 and 2019, and heavy alcohol consumption increased by 2.3% per year among nonpregnant women. However, binge drinking increased 8.9% per year and heavy alcohol consumption increased 11.6% per year among pregnant women.5 and psychosocial stressors6 that may have been exacerbated by the COVID-19 pandemic.Study limitations include the cross-sectional design, self-reported alcohol consumption, and wide CIs for estimates in 2019 and 2020. These results suggest worsening behavioral risks among pregnant women, potentially owing to changes in socioeconomic


Both superparamagnetic iron oxide nanoparticles (SPIO) and blue dye (BD) have been reported to cause skin staining after breast-conserving surgery. SPIO is a novel tracer that has been shown to identify sentinel lymph nodes (SLNs) in patients with breast cancer. Our study was the first to compare the incidence and size of skin staining between the two tracers. We reported on these outcomes in a preplanned secondary analysis of a prospective clinical trial in which women received both SPIO and BD. This study investigated whether there was a difference in the incidence and size of skin staining between SPIO and BD after SLN-dissection. In all, 270 women were operated on with breast-conserving surgery and received SPIO, and 204 of these women also received BD. After 24 months of follow up, there was no statistically significant difference between the two tracers with regard to the size and incidence of skin staining.2 (p = 0.56), while 51 (25.0%) had a BD stain with a median size of 8.5 cm2 (p = 0.93). The incidence and size of SPIO and BD staining decreased over time reciprocally. At 24 months, the incidence and median size of SPIO was 23 (8.6%) and 4 cm2, respectively. For BD, the incidence was 14 , and the median size was 3.5 cm2 (p = 0.18). There was, therefore, no statistically significant difference in the incidence or size of skin staining between SPIO and BD over time.Superparamagnetic iron oxide nanoparticles (SPIO) are a tracer for sentinel lymph node (SLN) detection. In a preplanned secondary analysis of a prospective clinical trial (SentiDose) we reported on skin staining after SPIO and blue dye (BD) injections. For SPIO, either a 1.5 mL retroareolar injection on the day of surgery or a 1.0 mL peritumoral/retroareolar injection 1–7 days before surgery was given. A 1.0 mL sub-/intradermal periareolar injection of BD was also administered to all these women. Staining was then assessed at 6, 12 and 24 months after surgery. A total of 270 women received SPIO and were operated on with breast-conserving surgery. Of these, 204 women also received BD. A total of 58 (21.5%) women had an SPIO stain 6 months postoperatively with a median size of 6.8 cm Seactions ,7,8,9. Ieactions ,11,12. 99 +/− BD as a background control. In this study, the SLN detection rates at lower doses were found to be comparable to Tc99 +/− BD. Following a 1.5 mL retroareolar injection, the detection rate was 97.5%, and it was 100% after a 1.0 mL peritumoral injection. This was comparable to Tc99 +/− BD. The longitudinal follow-up of skin staining after breast-conserving surgery with SPIO and BD were predefined secondary endpoints. Skin staining after an SPIO injection has previously been a concern as has been the case with BD ,11,13,14The primary outcome of this predefined analysis from the SentiDose study (SentiColor subprotocol) was to report on the incidence, duration and size of skin staining in the SentiDose patient population injected with both SPIO and BD. The secondary outcomes were to determine the predictive factors for SPIO staining and to investigate if different injection techniques could prevent skin staining.99 were used in all women, while BD was used as an adjunct according to local routines or surgeon preferences. Inclusion criteria were primary breast cancer (cT0–2cN0cM0) and Eastern Cooperative Oncology Group (ECOG) performance status 0–2. Women with previous ipsilateral breast or axillary surgery and/or radiation and neoadjuvant chemotherapy were excluded. Pregnant women, patients with iron sickness, patients who underwent mastectomy either primarily or within six months of initial surgery were excluded in this follow-up part of the SentiDose trial. The study was approved by the Uppsala University regional ethics committee (Decision Number 2017/063).Between 2017 and 2019, all women in the SentiDose trial  undergoi®/Magtrace®  at different time points using different injection techniques [99 +/− BD according to each site’s routine. BD was given as a 1.0 mL sub-/intradermal or retroareolar injection.In the SentiDose trial, SLN detection rates were compared after injecting two different doses of SiennaXPchniques . SPIO wa99) was implemented to define additional SLNs. The Sentimag probe was used during surgery to localize the SLN, and a gamma probe was subsequently used to identify any residual SLNs with radioactive signal. All magnetic, radioactive, blue, or brown SLNs were excised. The conventional cutoff of 10% of the SLNs with the highest signal (SPIO or Tc2) were followed up by telephone interviews 6, 12 and 24 months after surgery. If there was no staining, brown (SPIO) or blue (BD), on the first visit three to four weeks after surgery, no further follow-up was conducted. Follow-up was also ended when staining disappeared or at 24 months. Mean staining size calculations included only women with a stain at each time point. SLN detection rates have been reported elsewhere [Patient and tumor characteristics are presented in lsewhere . This malsewhere .® . Staining was analyzed in women with BCS. Descriptive statistics were performed with means  or medians (range) of continuous variables, and, depending on data distribution, statistical analyses were based on medians. Continuous data were analyzed using nonparametric tests. Dichotomous data were analyzed with Pearson chi-square for nonpaired observations and McNemar’s test for paired observations. Spearman´s rho test was used to measure the correlation between predictive factors for skin staining. Data analyses were performed using SPSSIn total, 271 women were operated on with BCS in the SentiDose trial, and one woman was later excluded due to a conversion to a mastectomy. Patient characteristics are presented in 2  and a median of 6.8 cm2 (range of 1–88). Between the 6- and 12-month controls, one woman had a mastectomy, and one died. Both of these women had an SPIO stain but no BD stain at 6 months. The corresponding data for SPIO staining at 12 and 24 months were 41/268 (15.3%) with a mean size of 5.9 cm2  and a median of 4 cm2 (range of 1–28 cm2) and 23/268 (8.6%) with a mean size of 6.4 cm2  and a median of 4 cm2 (range of 0–20 cm2)  and a median of 8.5 cm2 (range of 3–25 cm2). Between the 6- and 12-month controls, one woman with a BD stain but without an SPIO stain was lost to follow-up. The corresponding data for BD staining at 12 and 24 months were 32/201 (15.9%) with a mean size of 4.2 cm2  and a median of 4 cm2 (range of 0–9 cm2) and 13/201 (6.3%) with a mean size of 4.9 cm2  and a median of 3.5 cm2 (0–15 cm2)  and 12 vs. 24 months . The trend was similar for BD with the following corresponding numbers 25% vs. 15.9% and 15.9% vs. 6.3% with a respective p-value of >0.0005 for both comparisons. At six months, 58/270 (21.5%) women had an SPIO skin stain with a mean size of 12.6 cm–20 cm2) . At six –15 cm2) . When co–15 cm2) . There wp = 0.011) . The median size of the skin staining for the separate volumes and injection techniques for SPIO are shown in With regard to SPIO dosing, there was a significant difference between the 1.5 mL and 1.0 mL SPIO cohorts with reference to the incidence of skin staining at 6 months; there was an incidence of 34/129 (26.4%) versus 24/141 (17%) (= 0.011) . The corp = 0.004), but the difference had disappeared at 24 months to 0.098 (Spearman’s rho)  (p = 0.111). A low BMI showed a statistically significant positive correlation with skin staining at 6 months of 0.176 (Spearman’s rho)  (2 for SPIO and 25% with a median size of 8.5 cm2 for BD. Both SPIO and BD stains diminished in a similar fashion over time. The incidence and median size of SPIO staining at 24 months was 8.6% (4.0 cm2) and 6.3% (3.5 cm2) for BD.This study is, to our knowledge, the largest prospective study in which the incidence of skin staining with both SPIO and BD were followed up in parallel. In this study, more than 200 women received both SPIO and BD. There were no significant differences in incidence or size of skin staining when comparing SPIO and BD as tracers for SLNB. After 6 months, the incidence was 21.5% with a median size of 6.8 cmA lower volume of SPIO resulted in lower rates and smaller sizes of skin staining that disappeared faster. A peritumoral injection resulted in a lower incidence of skin staining compared to a retroareolar injection. The lowest incidence and smallest skin stains were noted when a 1.0 mL peritumoral injection was used. However, no statistical analysis was carried out in this subgroup due to the low number of women in the group. Further, a low preoperative BMI was a predictive factor for an increased risk of skin staining. A possible explanation is that the dispersion of SPIO in a larger breast seems to result in less uptake by the skin lymphatics and the removal of the bulk of SPIO when performing the BCS. In earlier studies, 35 to 41% of women were reported to have BD staining at 12 months along with 8.6% after 36 months. However, none of the women reported a cosmetic or psychological problem relating to the BD staining ,14. LongThe preoperative injection of SPIO compared to perioperative administration was associated with the identification of more SNs, and no extra intraoperative time or a massage at the injection site was required for the tracer to migrate to the axilla. This resulted in a shorter operating time with no consequent problems relating to tracer spillage or the diminished visualization of the SN as experienced with other methods such as t ICG .A further concern with SPIO usage is the likelihood of MRI artifacts due to SPIO´s paramagnetic properties ,19. A peA potential limitation in our study was the possible risk of reporting bias. The follow-up was conducted by telephone interviews. The initial status of staining at the first follow-up at two to four weeks after surgery was documented in the clinical register form (eCRF). If the medical record clearly stated that no stain was visible, then no further follow-up was initiated. Furthermore, the study protocol did not mandate the use of BD. While this restricted the numbers in the study, it was more in line with real world data that show that surgeons familiar with the isotope are often hesitant about adding BD to avoid its known adverse effects. It might have been that the use of BD in all the patients could have affected the reported outcomes, but this was a conscious decision of the investigators to align with optimal patient outcomes.To summarize, no differences in either incidence or size of skin staining were noted when comparing SPIO and BD after 6, 12 and 24 months of follow up. For both tracers, the staining diminished or disappeared in a similar manner over time. A lower dose of SPIO resulted in a lower incidence, a smaller size and faster diminishing of staining. With the benefits of no need for nuclear medical facilities, detection rates similar to the dual technique and the possibility to inject well before surgery, SPIO appears to be an appealing tracer choice for sentinel lymph node surgery.


Tumor spread through air spaces (STAS) in lung adenocarcinoma is a novel mechanism of invasion. STAS has been proposed as an independent predictor of poor prognosis. The aim of this study was to evaluate the correlations between STAS status and other clinicopathologic variables and to assess the prognostic implications of STAS and the distance from the edge of the tumor to the farthest STAS in patients with resected lung adenocarcinoma.This is a single-institution retrospective observational study. We included all patients with resected lung adenocarcinoma from January 2017 to December 2018 at La Paz University Hospital. The cut-off for the distance from the edge of the tumor to the farthest STAS was 1.5 mm and was assessed by the area under the receiver operating characteristic curve.P = 0.035) and absence of lepidic pattern (P = 0.022) were independently associated with the presence of STAS. The median recurrence-free survival (RFS) was 48.06 months [95% confidence interval (CI) 33.58 months to not reached]. STAS-positive patients had shorter median RFS [39.23 months (95% CI 29.34-49.12 months)] than STAS-negative patients (not reached) (P = 0.04). STAS-positive patients with a distance from the edge of the tumor to the farthest STAS ≥1.5 mm had an even shorter median RFS [37.63 months (95% CI 28.14-47.11 months)]. For every 1 mm increase in distance, the risk of mortality increased by 1.26 times (P = 0.04).A total of 73 patients were included. STAS was found in 52 patients (71.2%). Histological grade 3 (Histological grade 3 and absence of lepidic pattern were independently associated with the presence of STAS. STAS was associated with a higher risk of recurrence. The distance from the edge of the tumor to the farthest STAS also had an impact on overall survival. •Lung adenocarcinoma patients with STAS had higher risk of recurrence.•Patients with STAS and a distance from the edge of the tumor to the farthest STAS ≥1.5 mm had an even shorter RFS.•The distance from the edge of the tumor to the farthest STAS also had an impact on overall survival. Currently, several studies have focused on the relationship between STAS and prognosis.,,,In lung adenocarcinoma, there are different surgical procedures such as sublobar resection, lobectomy and pneumonectomy depending on the tumor features and the patient’s overall condition.The aim of this study was to assess the correlation between STAS status and other clinicopathologic variables. Furthermore, we also expected to explore whether STAS presence and the distance from the edge of the tumor to the farthest STAS were reliable prognostic factors of survival in patients with lung adenocarcinoma.This is a single-institution retrospective observational study. We included all patients with resected lung adenocarcinoma from January 2017 to December 2018 at La Paz University Hospital, Madrid (Spain). Patients were aged ≥18 years. The diagnosis of lung adenocarcinoma was confirmed histologically. Data regarding clinical and demographic characteristics, type of surgery and pathological features were obtained from the medical records of each patient. Staging was carried out in accordance with the standards of the American Joint Committee on Cancer, 8th Edition. Histological grading was measured using the grading system developed by The International Association for the Study of Lung Cancer (IASLC)This study was approved by the Ethics Committee of the La Paz University Hospital (code HULP: PI-4843), and was conducted in accordance with the ethical standards of the Helsinki Declaration by the World Medical Association.Median value (interquartile range) and frequency (percentage) were provided for the description of continuous and categorical variables, respectively. We used descriptive statistics to calculate the incidence of STAS. The distance from the edge of the tumor to the farthest STAS was also measured . The cutComparisons of categorical data between patients with and without STAS were carried out with the chi-square or Fisher’s exact test. Variables that achieved statistical significance in the univariate analysis and other variables considered of interest were included in the multivariate analysis using the logistic regression model. The logistic regression model was carried out to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for clinicopathologic variables associated with STAS status.P values < 0.05 were considered statistically significant. All statistical analyses were carried out using SPSS v.25.RFS was calculated from the date of diagnosis until first recurrence  or death due to any cause. OS was calculated from the date of diagnosis to the date of death from any cause. RFS and OS were compared among patients with and without STAS. Survival was estimated using the Kaplan–Meier method and described using median with 95% CI. A Cox regression was carried out to estimate the hazard ratios (HRs) and the 95% CIs. All the tests were two-sided, and .A total of 73 patients were included. STAS was found in 52 patients (71.2%). Baseline clinical and demographic characteristics, type of surgery, pathological features and molecular alterations of the patients with and without STAS are summarized in Table 1n = 44, 60.3%) were males with a median age of 68 years (range 42-85 years). A total of 60 patients (82.2%) were smokers or former smokers. Most patients  had pathological stage I, 13 patients (17.8%) had pathological stage II and 8 patients had pathological stage III (10.9%). The minority  had confirmed nodal involvement. Only one patient (1.4%) had positive surgical margins. Regarding histological grading, approximately half of the patients had grade 3  and half of the patients had grade 2  with a few patients with grade 1 . The existence of lymphovascular and perineural invasion occurred in 20.5% and 4.1% of the patients, respectively. The most frequent histological pattern was acinar . Around one-third of the patients  had lepidic pattern, another one-third of patients  had solid pattern, 20 patients (27.4%) had papillary pattern and 20 patients (27.4%) had micropapillary pattern. In terms of molecular alteration, eight patients (11%) had EGFR mutations, three patients (4.1%) had ALK mutations and no patient had ROS1 mutations. Almost half of the patients had PD-L1 expression <1% , 20 patients (27.4%) had PD-L1 expression between 1% and 49% and 19 patients (26%) had PD-L1 expression ≥50%. Regarding perioperative treatment, 17 patients (23.3%) received adjuvant chemotherapy and 2 (2.7%) patients received neoadjuvant chemotherapy.The majority , in patients with nodal involvement , in patients with histological grade 3 (88.2% versus 56.4%), in patients with lymphovascular (86.7% versus 67.2%) and perineural invasion (100% versus 70%), in patients with absence of lepidic pattern (83% versus 50%), in patients with solid (92.3% versus 59.6%) and micropapillary patterns (75% versus 69.8%), in patients with PD-L1 expression ≥50% (78.9% versus 70 and 67.6%), in patients with EGFR wild type (72.3% versus 62.5%) and in patients with ALK mutations (100% versus 70%).Sublobar resection  was carried out in 14 patients (19.2%) and lobectomy in 59 patients (80.8%). Interestingly, STAS was slightly more prevalent in sublobar resections  . RegardiP = 0.004), solid pattern (P = 0.003) and absence of lepidic component (P = 0.003) were significantly associated with the presence of STAS in the univariate analysis (P < 0.001), we did not enter solid pattern in the final multivariate model. We also included other variables considered of interest such as age and sex in the multivariate analysis.Among the clinicopathological characteristics, histological grade 3 , P = 0.022] were independently associated with the presence of STAS ,  of STAS .Table 2Mn = 14, 51.9%), followed by the brain , the pleura , the lymph nodes  and bone . The median RFS was 48.06 months (95% CI 33.58 months to not reached). STAS-positive patients had shorter median RFS  than STAS-negative patients (not reached), with statistically significant differences (P = 0.04) (P = 0.05). Specifically in patients who underwent lobectomy, STAS-positive patients also had shorter median RFS than STAS-negative patients (median 39.23 months versus not reached), but without statistically significant differences (P = 0.11). Taking into account the distance from the edge of the tumor to the farthest STAS in patients who underwent lobectomy, for every 1 mm increase in distance, the risk of recurrence increased by 1.17 times [HR 1.17 (95% CI 1.01-1.36 times)] with statistically significant differences (P = 0.03).A total of 27 patients (37%) had confirmed recurrence of the disease, of whom 21 patients underwent lobectomy and 7 patients underwent sublobar resection. Regarding the pathological stage of patients who had confirmed recurrence of the disease, 12 patients had stage I , 7 patients stage II  and 8 patients stage III . The most common site of recurrence was the lung ( = 0.04) . The risP = 0.02) (P = 0.02). According to the type of surgery, patients with STAS who underwent a sublobar resection had shorter RFS (48.06 months) than patients with STAS who underwent a lobectomy (39.23 months), but without statistically significant differences (P = 0.83). Specifically in patients who underwent lobectomy, STAS-positive patients with a distance from the edge of the tumor to the farthest STAS ≥1.5 mm also had shorter median RFS than STAS-negative patients or STAS-positive patients with a distance from the edge of the tumor to the farthest STAS <1.5 mm (median 37.63 months versus not reached), with statistically significant differences (P = 0.02). The risk of recurrence was 2.6 times higher in patients with STAS and a distance from the edge of the tumor to the farthest STAS ≥1.5 mm , with statistically significant differences (P = 0.02).The cut-off for the distance from the edge of the tumor to the farthest STAS was 1.50 mm. A total of 36 patients (49.3%) had STAS at a distance from the edge of the tumor to the farthest STAS ≥1.5 mm, of whom 6 patients underwent sublobar resection and 30 patients underwent lobectomy. STAS-positive patients with a distance from the edge of the tumor to the farthest STAS ≥1.5 mm had shorter median RFS [37.63 months (95% CI 28.14-47.11 months)] than STAS-negative patients or STAS-positive patients with a distance from the edge of the tumor to the farthest STAS shorter than 1.5 mm (not reached), with statistically significant differences ( = 0.02) . The risP = 0.04). Specifically in patients who underwent lobectomy, STAS-positive patients also appeared to have shorter OS, but medians were not reached either. In addition, the distance from the edge of the tumor to the farthest STAS also had an impact on OS in these patients. For every 1 mm increase in distance, the risk of death also increased by 1.26 times [HR 1.26 (95% CI 1.00-1.59)] with statistically significant differences (P = 0.04).A total of 15 patients (20.5%) had died, of whom 1 patient underwent sublobar resection and 14 patients underwent lobectomy. The median OS was not reached. STAS-positive patients appeared to have shorter OS than STAS-negative patients, however medians were not reached. The distance from the edge of the tumor to the farthest STAS had an impact on OS. For every 1 mm increase in distance, the risk of death increased by 1.26 times [HR 1.26 (95% CI 1.00-1.59)] with statistically significant differences . Therefore, further studies on the relationship between STAS and other molecular alterations are needed. Third, the follow-up was not enough to obtain results of OS, because we only included patients since 2017. Despite these limitations, this study provides relevant information about the incidence of STAS and the relationship between STAS and other clinicopathological characteristics and molecular alterations. In addition, our study reaffirms the poor prognosis related to the presence of STAS in adenocarcinoma patients treated with surgery and provides relevant information on the importance of taking into account the distance from the edge of the tumor to the furthest STAS, since the greater the distance, the worse the survival.In conclusion, histological grade 3 and absence of lepidic pattern were independently associated with the presence of STAS. In addition, the presence of STAS was associated with a higher risk of recurrence in patients with lung adenocarcinoma treated with surgery. In particular, STAS-positive patients with a distance from the edge of the tumor to the farthest STAS ≥1.5 mm had an even shorter median RFS. Furthermore, the distance from the edge of the tumor to the farthest STAS also had an impact on survival. Further prospective studies including data from multiple centers are needed to derive definitive conclusions.


The adverse effects of ozone and cold temperature on asthma morbidity in Taiwan are still inconclusive. (2) Methods: This retrospective study included patients who had asthma emergency room visits (ERVs) from 1 January 2016 to 31 December 2019 in a regional hospital in Taiwan. The short-term negative effects were estimated using Distributed Lag Non-Linear Models (DLNMs) for the relative risks (RRs) of asthma ERVs associated with PM2.5, ozone and cold temperature exposures within 5 days. (3) Results: There was a significant association between a 10 ppm increase in PM2.5 exposure and asthma ERVs at a 2-day lag : 1.051–1.294). There was a significant association between ozone and asthma ERVs at a 1-day lag . The ambient temperature in cold weather compared with the temperature of minimum asthma ERV showed an RR of 1.214, 95% C.I.: 1.009–1.252 at a 1-day lag. (4) Conclusions: This study provides evidence that short-term exposure to fine suspended particulates, ozone and inverse temperature is associated with asthma exacerbation.(1) Background: The acute effects of ozone, cold temperature and particulate matter less than 2.5 μm (PM Asthma is a chronic respiratory disease that affects more than 350 million people worldwide, and its incidence is on the rise. It is reported to kill approximately 383,000 people each year . Acute aFor chronic asthma, the estimated prevalence is the highest in the African region 11.3%), but the lowest in the Southeast Asia region (8.8%) %, but th. The pre2.5) in the air, the higher the relative risk of respiratory diseases [2.5 as a first-class carcinogen [Exposure to air pollution can lead to respiratory and cardiovascular diseases, lung cancer ,9,10,11 diseases . In 2013rcinogen .2.5 and ozone (O3). Traffic and power generation are the main sources of urban air pollution, and traffic-related air pollution (TRAP), as well as the air pollutants O3, nitrogen dioxide (NO2) and PM2.5, can induce airway inflammation [Motor vehicle combustion, fossil fuel (traffic exhaust), power plants or other industrial processes may be the main sources of PMammation .2.5 was related to asthma emergency room visits (ERVs) in Taipei [2.5 and ozone in southern Taiwan [A past study found that PMn Taipei . Youngern Taiwan . Studiesn Taiwan ,17,18,19n Taiwan .Taoyuan City is an urban area of Taiwan located in southern Taipei, and New Taipei cities have higher TRAPs. Longtan District is located in southern Taoyuan. In the special terrain surrounding the U sharp mountain, the seasonal wind carries air pollutants from mainland China and Linkou District that is difficult to clean out in the winter. Several factories for wafer manufacturing which use ozone water for wafer washing are located in the Longtan District. The air pollution and climate factors that may cause asthma attacks with delayed effects need to be studied. The relationship between asthma ERVs and air pollution or climate conditions in special areas is worthy of study.The aim of this study focused on the relationship between asthma ERVs, ambient pollutants and climate conditions for a period of four years in Taiwan. The unique terrain caused air pollutants to gather via seasonal winds in winter, which resulted in asthma attacks. Although the government has focused on reducing air pollution for years, some air pollutants are still not targeted by the WHO’s air pollution guideline values, and aggressive policies to reduce them that would promote citizens’ health have not yet been introduced.We analyzed daily asthma ERVs data for the time period 1 January to 31 December from 2016 to 2019 at Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan. The regional hospital is located within the southern area of Taoyuan City in Taiwan and has more than 60,000 ERVs yearly; it is the only hospital with an emergency department in southern Taoyuan City. The Longtan District is a sector of hilly terrain located in the southern region of Taoyuan, with the highest height in the southeastern part, the lowest height in the northwestern part, higher terrain on both sides and 124,442 residents in 2021 [2.5, O3, NO2, sulfur dioxide (SO2), carbon monoxide (CO), relative humidity (RH) and ambient temperature. The data were obtained from the Environmental Protection Administration’s (EPA) Taiwan Quality Monitoring Network [The daily air pollutant gas data were obtained from the Taiwanese Environmental Protection local air quality monitoring station in Longtan of Taoyuan City , which is the nearest station (approximately 2.35 km) to Taoyuan Armed Forces General Hospital. Air pollutants include PMWe used ERVs data, including information from 1 January 2016 to 31 December 2019. The occurrence of ERVs was retrieved via International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes 493 and ICD-10-CM code J45. The flowchart of this study is described in 2.5, PM10, O3, CO, NO2, SO2, air temperature and relative humidity). The correlations between air pollutants and meteorological factors were assessed. We set the exclusion criteria at |r| > 0.8 to reduce the collinearity problem between each variable. The correlations were above 0.8 between PM2.5 and PM10 as well as between NO2 and CO, and we excluded PM10 and CO  and air temperature used multivariable DLNM analysis-adjusted wind speed, relative humidity, holiday, seasonality and time trends, and lag was set at 0–5 days [Descriptive statistics of asthma ERVs, air pollutants and meteorological factors were evaluated . The dis0 and CO . The lev0–5 days . The DLN0–5 days . PoissonWe counted the numbers of asthma ERVs in pediatric (0–17 years old), adult (18–64 years old) and older asthma patients (>65 years old). According to sex, we also counted the numbers of asthma ERVs in male and female patients. The cold season was defined as November to April, and the warm season was defined as May to October.2.5 was 26.97 ppm in April. The mean O3 values exhibited twin peaks of 37.89 ppb in April and 39.09 ppb in October  asthma ERVs were discharged after treatment, 296 (22.41%) asthma ERVs required hospitalization, 9 asthma ERVs were transferred to other hospitals, 19 asthma ERVs were discharged against medical advice and 1 asthma ERV resulted in death . The max October . 2.5 exposure had a positive relationship with asthma ERVs, with an RR of 1.166 : 1.051–1.294) for a 10-unit increase with a 2-day lag. O3 exposure had a positive relationship with asthma ERVs, with an RR of 1.179 (95% C.I.: 1.034–1.345) for a 10-unit increase with a 1-day lag. The ambient temperature in cold weather (25%:18 °C) was compared with MAT of 26 °C  with a 1-day lag. NO2 exposure had no significant relationship with asthma ERVs, with an RR of 1.238 (95% C.I.: 0.881–1.74), for a 10-unit increase with a 1-day lag (2.5 of 1.125 (95% C.I.: 0.933–1.358); O3 of 1.027 (95% C.I.: 0.836–1.262) and NO2 of 0.776 (95% C.I.: 0.464–1.293)  at a 2-day lag in pediatric asthma patients, 1.253 (95% C.I.: 1.037–1.515) at a 1-day lag in older asthma patients and 1.281 (95% C.I.: 1.087–1.509) at a 4-day lag in adult asthma patients. The extremely cold temperature (1%: 10 °C)) association was evident in elderly asthma patients, with an RR of 1.378 (95% C.I.: 1.049–1.811) compared with MAT at a 1-day lag and an RR of 1.193 (95% C.I.: 1.037–1.373) at a 1-day lag in male asthma patients, whereas no association was observed among children or females.PM-day lag . The lag4–1.293) . The RR 2.5 was 1.231 (95% C.I.: 1.061–1.244) at a 2-day lag, and the RR of O3 was 1.33 (95% C.I.: 1.106–1.599) at a 1-day lag every 10-unit increase in female asthma patients. The RR of NO2 in the warm seasons was 2.308 (95% C.I.: 1.132–4.705) every 10 units, without lag. The RR of PM2.5 in the cold season was 1.2 (95% C.I.: 1.051–1.37) every 10 units, with increased lag at 2 days; the RR of O3 in cold seasons was 1.222 (95% C.I.: 1.007–1.484) every 10 units, with increased lag at 1 day and the RR of cold temperature (13 °C) compared with 18 °C in cold seasons was 1.129 (95% C.I.: 1.027–1.24) at a one-day lag.The RR of PM2.5. Chemicals with oxidant-generating capabilities affect the human respiratory and immune systems [Our study suggested that the ozone and cold weather related to asthma ERVs are associated with PM systems . Recent  systems ,25.Asthma exacerbation is defined as a worsening of shortness of breath, cough, wheezing, or chest tightness. If patients don’t receive effective treatment immediately, it will increase airflow resistance, causing an increase in breathing workload, gas exchange inefficiency and respiratory muscle fatigue and result in hypercapnic and hypoxemic respiratory failure. Acute asthma attacks are a significant public health problem and influence quality of life, affecting patients and families through causing absences from labor and school, frequent ERVs, hospitalizations and possible death ,26.2.5 may contain toxic substances from combustion, including acids, metals and nitrates. These ingredients can accumulate in the lungs and cause allergies with increased immunoglobin E and inflammation [2.5 concentrations have been shown to be higher in cold weather [2.5 was related to asthma ERVs in Taipei [2.5 in the winter season. The mean daily PM2.5 concentration is at its highest in April due to residents worshiping their ancestors by burning incense and joss paper during the Qingming Festival on 5 April. The highway crosses the Longtan District with higher TRAPs. A lag of only one day in PM2.5 exposure was associated with acute asthma attacks in older asthma patients, which means that older asthma patients are more sensitive to PM2.5 changes and have weaker respiratory tract defenses than pediatric and adult asthma patients. Adult asthma patients carrying a heavy workload could initially go to the clinic and be sent to emergency departments, but symptoms would worsen after several days, and this would cause an even longer lag for asthma ERVs.PM carries metal components, and organic matter has the ability to generate oxygen free radicals, which can stimulate cells to produce ROS . ROS-indammation ,29. PM2. weather , and ourn Taipei . Our stu2. Ozone triggers asthma because it is very irritating to the lungs and airways. It is well-known that ozone concentration is directly related to asthma attacks, reducing lung function and causing ERVs to be required for medication treatment [3 can promote airway infections and increase the risk of asthma attacks [3 concentrations were associated with a higher risk of asthma in young adults. Women aged 40 to 64 years had the highest relative risk of ERVs, with an RR of 1.21 (95% CI 1.05–1.39) [3 was related to asthma ERVs in the female patients and in the cold seasons in our study.Ozone, a gas, is one of the most common air pollutants. It is most common in cities where there is heavy road traffic . It is areatment . Acute oreatment . Exposur attacks ,34. A si attacks . The mea attacks . The pot05–1.39) . HoweverExtreme temperatures are related to ERVs in the United States , and col2 was mainly from motor vehicle emissions and was not related to asthma ERVs in the four-year period. The potential reason was O3 formation through photochemical reactions with NO2 and volatile organic compounds at high altitudes [2 (12.11 ppm) than that in Taipei (19.83 ppm) [2 was related to asthma ERVs in the warm season, the potential reason was that NO2 transferred to O3, resulting in higher O3 concentrations in the warm season.NOltitudes , which rtudes [2 .11 ppm t2.5, ozone and cold temperature on asthma ERVs and discussed the different effects of sex and age.We used asthma ERVs of a single regional hospital, urban air pollution and climate data to analyze the association by distributed lag nonlinear time series models. The results demonstrated the harmful effects of short-term exposure to PM2.5 and O3 showed increasing trends, and the cumulative effect over time needs to be evaluated in the future. Fifth, the special terrain of Longtan District and the seasonal winds in Taiwan resulted in increased asthma ERVs, and different areas in Taiwan may have different levels of air pollution. A past study showed that air pollution was related to ERVs of respiratory disease and upper respiratory tract infections in the basin terrain of the Taipei area [There were some limitations to our study. First, the daily detailed treatments for asthma were not collected in our study; this may have been related to asthma attacks lasting for days, which may have caused negative effects due to the delay. Second, infection, seasonal change, smoking and in-kitchen smoking were significantly related to acute asthma symptoms and ERVs . Smokingpei area ,43. The This study showed positive relationships between short-term air pollutants of fine PM, ozone, climate factors of cold temperature exposure and acute asthma exacerbation. Since the mean fine PM and ozone concentrations have decreased in recent years due to the increased control over the quality of air in Taiwan, adverse effect concentrations have not yet been achieved, according to WHO air pollution guideline values , in rece