During the COVID-19 pandemic, US schools have been encouraged to take a layered approach to prevention, incorporating multiple strategies to curb transmission of SARS-CoV-2. Using survey data representative of US public K–12 schools (N = 437), we determined prevalence estimates of COVID-19 prevention strategies early in the 2021–22 school year and describe disparities in implementing strategies by school characteristics. Prevalence of prevention strategies ranged from 9.3% (offered COVID-19 screening testing to students and staff) to 95.1% (had a school-based system to report COVID-19 outcomes). Schools with a full-time school nurse or school-based health center had significantly higher odds of implementing several strategies, including those related to COVID-19 vaccination. We identified additional disparities in prevalence of strategies by locale, school level, and poverty. Advancing school health workforce and infrastructure, ensuring schools use available COVID-19 funding effectively, and promoting efforts in schools with the lowest prevalence of infection prevention strategies are needed for pandemic preparedness. To prevent transmission of SARS-CoV-2, the virus that causes COVID-19, in school settings and maintain in-person learning during the 2021–22 school year, US schools implemented a range of COVID-19 prevention strategies  might require personnel with medical and public health expertise and existing infrastructure for offering services. For example, implementation studies of school-based influenza vaccination programs have underscored the importance of dedicated staff and program infrastructure for securing supplies and necessary funding, disseminating materials , communicating about the program to students and families, and managing logistics  was initiated to better understand implementation and effectiveness of infection prevention strategies in K–12 school settings , whose feedback was incorporated in the final survey. Each participant was given a unique link to complete the survey online. Of the 1,602 schools invited to participate, 437 (27%) completed the survey. The primary survey respondents were principals  and school nurses . Respondents were offered an electronic gift card valued at $50 for their time and effort. This study was approved by the Institutional Review Board of ICF, a research and evaluation consulting firm, in accordance with CDC’s policies.>76% of students eligible for free or reduced-price meals, mid-poverty schools had 26%–75% eligible, and low-poverty schools had <25% eligible  assessed through the survey questions  Table 1.2 tests to identify differences. We ran separate weighted logistic regression models with each COVID-19 prevention strategy as the dependent variable and school-level characteristics  as the independent variables, controlling for new cases per 100,000 persons in the previous 7 days in the county. We selected independent and control variables on the basis of a review of literature on factors influencing implementation of infection prevention strategies in schools; selected controls satisfied criteria for confounder selection (https://www.r-project.org) by using the survey package  , as have challenges   were more likely to have certain prevention strategies in place even after adjustment for other school- and county-level characteristics. Schools with an SBHC might be better equipped to respond to public health emergencies and provide certain health services . The National Association of School Nurses and AAP recommend that every school have a full-time school nurse ; however, most school-level characteristics were not associated with survey participation based on our nonresponse analysis  Table 2,Despite those limitations, our study expands understanding of COVID-19 prevention strategies used by schools during the 2021–22 school year, by using data from a population-based sample drawn to be representative of K–12 public schools in the United States. Our study documents strategy implementation at the school level, as opposed to the school district level. Although COVID-19 prevention policies are likely set at the school district level, variation exists in what schools implement, and measuring implementation at the school-level can better capture what occurred in practice. Because survey administration coincided with the surge of the SARS-CoV-2 Delta variant, the period examined represents one of high community transmission nationally, which necessitated layered prevention strategies in all schools. Moving forward, schools might consider adapting to their local context and monitoring COVID-19 community levels to guide implementation of prevention strategies (Additional information about disparities in implementation of COVID-19 prevention strategies in public schools, United States, 2021–22 school year.


Telomere length (TL) has been reported to be associated with depression and cognitive impairment in elderly. Early detection of depression and cognitive impairment is important to delay disease progression. Therefore, we aimed to identify whether TL is associated with early subjective depressive symptoms and cognitive complaints among healthy elderly subjects. This study was a multicenter, outcome assessor-blinded, 24-week, randomized controlled trial (RCT). Measurement of questionnaire and physical activity scores and blood sample analyses were performed at baseline and after six months of follow-up in all study participants. Linear regression analyses were performed to identify whether early subjective depressive symptoms, cognitive complaints, and several blood biomarkers are associated with TL. Altogether, 137 relatively healthy elderly individuals (60–79 years old) were enrolled in this prospective RCT. We observed an approximate decrease of 0.06 and 0.11−0.14 kbps of TL per one point increase in the geriatric depression scale and cognitive complaint interview scores, respectively, at baseline and after six months of follow-up. We also found an approximate decrease of 0.08−0.09 kbps of TL per one point increase in interleukin (IL)-6 levels at baseline and after six months of follow-up. Our study showed that both early subjective depressive symptoms and cognitive complaints were associated with a relatively shorter TL in relatively healthy elderly individuals. In addition, based on our findings, we believe that IL-6 plays an important role in the relationship between shortening TL and early subjective depressive symptoms and cognitive complaints. Telomeres are regions of tandem repeats of the base pairs TTAGGG located at chromosomal ends and undergo attrition with each division of somatic cells . TherefoWe previously reported the randomized controlled trial (RCT) of the SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at-risk elderly people (SUPERBRAIN) , 14. In Therefore, we aimed to identify whether TL is associated with not only major depression or substantial cognitive decline and dementia but also with early subjective depressive symptoms or/and cognitive complaints in relatively healthy elderly subjects. This was possible because the SUPERBRAIN study initially excluded elderly individuals with major depression, dementia, or severe cognitive impairment from the study. In addition, we analyzed the relationship between various biomarkers related to geriatric diseases and TL.Between May 29 and August 20, 2019, among 152 randomly assigned relatively healthy elderly participants (60–79 years old), 137 individuals who had TL measured both at baseline and after six months of follow-up were finally included in this randomized controlled prospective study. The average subject age was 70.8 years, and 74.5% of subjects were women . The meaThe boxplot shows no significant difference in the TL between baseline and after six months of follow-up in the elderly subjects in this study . InteresWe estimated the questionnaire and physical activity assessment scores at baseline and after six months of follow-up in all elderly subjects our study. There were statistically significant differences in the GDS-KR, CCI, SPPB, KQOL, and NTR scores between baseline and after six months of follow-up because 6-month intervention programs were implemented . UnsurprWe identified significant negative correlations between the GDS-KR and CCI scores and TL both at baseline and after six months of follow-up in We also obtained values of several biomarkers at baseline and after six months of follow-up in all elderly subjects in the study. There were significant differences in the TNF-α and NfL values between baseline and after six months of follow-up . MoreoveMultivariable linear regression analysis showed that higher GDS-KR and CCI scores and serum IL-6 levels were independently associated with a shorter TL both at baseline and after six months of follow-up in the relatively healthy elderly participants .We found that early and subjective depressive symptoms and cognitive complaints are associated with a relatively shorter TL among relatively healthy elderly individuals in the randomized controlled prospective SUPERBRAIN study. In addition, when analyzing the relationship between blood levels of several biomarkers and TL, a shorter TL was related to increased systemic levels of IL-6. It is possible that six months intervention programs affected the rate of TL shortening. However, according to our findings, there was no statistically significant difference in TL between baseline and after six months of follow-up . We founWe measured scores related to subjective depressive symptoms using the 15-item GDS-KR and subjective cognitive decline with the CCI. The GDS is used widely as a screening instrument for early and subjective depressive symptoms in elderly , 26. ThePrevious studies have reported that depression is associated with accelerated cellular aging and short TL –9. It isDepression in the elderly is often associated with cognitive symptoms, which range from normal cognitive changes in aging to mild cognitive impairment to dementia , 23. In The precise mechanism underlying the correlation of shorter TL with depression, cognitive decline, and inflammatory cytokines remains unclear. However, although the complexity of the crosstalk between the inflammatory response and telomere shortening/dysfunction has not yet been fully revealed, evidence has led to the hypothesis that chronic inflammation interacts with TL in a bidirectional way . Namely,First, this study was not originally designed to investigate the relationship between TL and subjective depressive symptoms and cognitive complaints in the elderly. Second, since this study was a feasibility RCT, it will be necessary to confirm the results of our study by performing large-scale RCT in the future. Third, the period between the two TL measurements was relatively short. Therefore, long-term changes in TL could not be analyzed. Fourth, the relatively small sample size in the present study may have influenced the results.In conclusion, we showed that both early subjective depressive symptoms and cognitive complaints in relatively healthy elderly individuals were associated with a relatively shorter TL in the randomized controlled prospective SUPERBRAIN study. In addition, a shorter TL was associated with increased IL-6 levels in our study participants. We believe that IL-6, an inflammatory cytokine, plays an important role in the relationship of shortening TL with early subjective depressive mood and cognitive complaints. Although the results will need to be verified through a large-scale RCT in the future, we believe that our findings will help prevent and treat depression and cognitive impairment in the healthy elderly.This study was a multicenter, outcome assessor-blinded, 24-week, RCT with a multi-arm parallel design performed in three hospitals and five public health centers across South Korea. The study participants were selected from among older adults who visited outpatient clinics or public health centers for memory complaints. As described in the Introduction, this study was originally designed to examine whether various outcomes were improved in the groups that received the FMI and HMI programs of the SUPERBRAIN compared with the control group. In a 1:1:1 ratio, participants were randomly assigned to the one of three groups: FMI, HMI, and control groups. Randomization was achieved through a permuted block randomization method, and the outcome assessors remained blinded to the assigned groups. Participants were instructed not to discuss their study involvement with the outcome assessor. We previously described the detailed study protocol , 14.The study was performed in accordance with the International Conference on Harmonization Good Clinical Practices Guidelines. Institutional review boards approved the protocol and consent forms at each institution before the study began. Written informed consent was obtained from all potential study participants before their enrollment. This trial was registered with ClinicalTrials.gov (NCT03980392) , 14.As reported in our previous study , 14, theTreatment history of depressive symptoms was defined as currently receiving treatment or having received treatment in the past for depressive symptoms. Hypertension was defined as a prescription for antihypertensive medication(s) or a measured systolic blood pressure > 140 mmHg and diastolic blood pressure > 90 mmHg. Diabetes mellitus was defined as a prescription of insulin or oral hypoglycemic medications, a high plasma glucose level (≥ 126 mg/dL), or a high glycated hemoglobin level (≥ 6.5%) after eight hours of fasting. Hyperlipidemia was defined as a prescription for lipid-lowering medications or high levels of total cholesterol (≥ 200 mg/dL), low-density lipoprotein cholesterol (≥ 130 mg/dL), and triglycerides (≥ 150 mg/dL) and low levels of high-density lipoprotein cholesterol (< 40 mg/dL). Heart disease was defined as a history of an acute coronary event or arrhythmia including atrial fibrillation or use of heart-related drugs. Stroke was defined as a history of cerebral infarction or hemorrhage such as intracerebral hemorrhage and subarachnoid hemorrhage.We obtained fasting blood samples from all participants at approximately 9 o’clock in the morning within four weeks before baseline and at the study endpoint. We previously described the detailed method of TL measurement as follows : At baseSerum biomarkers such as brain derived neurotrophic factor (BDNF), triggering receptor expressed on myeloid cells 2 (TREM2), interleukin (IL)-6, IL-18, insulin-like growth factor 1 (IGF-1), YKL-40 (chitinase-3-like protein 1), transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α), vascular endothelial growth factor (VEGF), neurofilament light chain (NfL), and monocyte chemoattractant protein 1 (MCP-1) were also measured by a quantitative sandwich enzyme-linked immunosorbent assay .Questionnaire and physical activity scores were measured at baseline and after six months of follow-up in all elderly participants in the study. Subjective depressive mood was assessed by the 15-item Geriatric Depression Scale revised Korean version (GDS-KR) . CognitiStudent’s t-test was performed to evaluate differences between values at baseline and after six months of follow-up. Box plots were used to visualize differences in TL and IL-6 levels at baseline and after six months of follow-up.Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off TL that predicted depressive symptoms requiring treatment in the elderly. We used TL as the test variable and the treatment history of depressive symptoms as the state variable (dependent variable) in the ROC curve analysis. The optimal cut-off TL was defined as showing the shortest distance from the upper left corner (where sensitivity=1 and specificity=1).Pearson’s correlation analysis was performed to evaluate the associations between TL and the questionnaire and physical activity scores and concentrations of blood biomarkers at baseline and after six months of follow-up.Scatterplots with a regression line were constructed to determine whether TL was associated with GDS-KR and CCI scores and IL-6 levels. Multivariable linear regression analyses were also performed to identify whether GDS-KR and CCI scores and serum IL-6 levels were independently associated with TL. In addition to separately including GDS-KR, CCI score, and IL-6 level, covariates such as sex, age, BMI, hypertension, diabetes, hyperlipidemia, heart disease, and stroke history were entered into the multivariable model. For a comparison with the multivariable linear regression results, univariable linear regression analysis was also performed using the same variables as those used in the multivariable analysis .A p-value < 0.05 was considered statistically significant. All statistical analyses were performed using R software version 4.1.2 and SPSS for Windows version 24.0 .Supplementary FiguresSupplementary Table 1


COVID-19 can have detrimental effects on immunosuppressed patients. Here, we evaluate the evidence regarding continuing immunomodulatory/biologic (IMBI) therapy in pregnant dermatology patients during the COVID-19 pandemic. Also, we discuss the risks of COVID-19 vaccination in pregnant dermatology patients on IMBI therapy. As indicated in this review, regarding continuing IMBI therapy in pregnant dermatology patients during the pandemic, there is no compelling reason for treating them differently than non-pregnant. The body of evidence indicates that mRNA COVID-19 vaccines are safe during pregnancy. Studies on rheumatology patients, a group that overlaps significantly with the dermatology group, provided essential findings. IMBI in a non-pregnant rheumatology patient was not associated with COVID-19 mortality (except for rituximab), and vaccination of the rheumatology patient during pregnancy improved the obstetric outcomes compared to the unvaccinated patient. Based on this data, it can be stated that after weighing the benefit–risk profile of the available COVID-19 vaccines, the recommendation for the pregnant dermatology patient speaks in favor of the COVID-19 vaccination. COVID-19 vaccine recommendations in pregnant dermatology patients on IMBI should not differ from those for their non-pregnant counterparts. Similar concerns were raised about the safety and efficacy of COVID-19 vaccination in these groups. Such individuals have been traditionally excluded from clinical trials, which made formulating recommendations challenging.The modulations of the maternal immune system in pregnancy may affect the response to viral infections such as COVID-19 ; a decreHere we discuss the effects of COVID-19 on maternal and fetal/neonatal outcomes and evaluate the evidence regarding the continuation of IMBI therapy for dermatologic conditions in pregnant persons diagnosed with COVID-19. We also discuss the evidence relevant to the risks of COVID-19 vaccination in pregnant patients on IMBI therapy for dermatologic conditions. Furthermore, we compare such evidence to that of non-pregnant patients on IMBI therapy.αI) , interleukin (IL)-17 , IL-4/13 inhibitors (dupilumab), and anti-IL-12/23 (ustekinumab)  is less than 2% of maternal infections . Shah an in 1.8% . Individ in 1.8% , which ecumented . The angcumented , 50. The3.p¼ 0.25), adjusting for demographics, comorbidity burden, and local infection rates (p¼0.04). Mortality rates were similar in the group of patients on biologics and matched controls. In another study, IMBI therapy was not associated with increased COVID-19 severity in patients with hidradenitis suppurativa  whether IMBI therapy increases the risk of COVID-19 or subsequent mortality and b) whether IMBI should be postponed or discontinued in patients diagnosed with COVID-19. Regarding the first question, a retrospective matched cohort study from Massachusetts showed that, overall, biologics were not associated with COVID-19  Guideline 169 for dermatologic conditions recommend the discontinuation of biologics in COVID-19-positive patients  recommends shielding for patients at the highest clinical risk: patients taking ⩾20 mg prednisolone  per day for >4 weeks or ⩾5 mg prednisolone  per day combined with another immunosuppressant, patients taking a combination of two or more immunosuppressants, patients taking cyclophosphamide, and patients on rituximab or infliximab for primarily skin conditions .4.Most professional associations concur that COVID vaccines are safe in the dermatology patient on IMBI . As noneA study suggested that there might be an association between COVID-19 vaccination and exacerbation of autoimmune bullous diseases (AIBDs) . Three-fαI  and anti-IL-12/23 (ustekinumab) biologics have been associated with a decrease in antibody levels. Prednisone at a dose of >20 mg per day diminished humoral responses to influenza vaccines in patients with systemic lupus erythematosus  were on biologics; in 22 of those (29.3%), the treatment was stopped at a median of 28 weeks’ gestation . Twenty-Antenatal systemic corticosteroids are administered to women at threat of preterm birth and fetal lung maturity and confer significant morbidity and mortality benefit for neonates . The REC6.Most authorities recommend that all unvaccinated people planning a pregnancy or those who are pregnant or recently pregnant undergo COVID-19 vaccination, and those who are vaccinated should receive booster doses when eligible , 89, 90.Experts suggest that women during pregnancy or postpartum should opt for mRNA vaccines, if accessible, as viral vector vaccines may cause thrombosis associated with thrombocytopenia . If mRNAThere are inadequate data on vaccine safety and efficacy in pregnant patients on IMBI. In a descriptive study, unvaccinated pregnant women with rheumatic and musculoskeletal diseases (RMD) and COVID-19 had a greater number of pre-term births compared with those fully vaccinated against COVID-19 . AdditioIn a report of two pregnant COVID-19-positive systemic lupus erythematosus patients, both women delivered healthy babies . One patNo data support that the COVID-19 vaccine response in a pregnant patient on IMBI differs from that in a non-pregnant counterpart. There is evidence that vaccination of a non-pregnant patient on IMBI provokes substantial humoral responses, even if the antibody titers generated are lower in patients on certain medications such as systemic corticosteroids. Most importantly, looking at the rheumatic disease group of patients, which overlaps significantly with the dermatologic disease group, IMBI in a non-pregnant patient was not associated with COVID-19 mortality (except for rituximab), and vaccination of the rheumatic patient during pregnancy improved the obstetric outcomes compared to the unvaccinated patient. Based on this data, it can be stated that after weighing the benefit–risk profile of the available COVID-19 vaccines, the recommendation for the pregnant dermatology patient speaks in favor of the COVID-19 vaccination.7.Several issues should be included in a consultation about the risks and benefits of discontinuing IMBI therapy:Scarcity of data on pregnancy during COVID-19 clinical trialsStudies showing that IMBI may not affect the course of COVID-19 in immunocompetent patients with dermatologic conditions Data showing that adverse pregnancy outcomes were infrequent and not associated with IMBI in IBD patients Risk of COVID-19 complications due to pregnancy (increased risk to a pregnant person of severe disease and death) or underlying conditions Risk of COVID-19 to the fetus or newborn (preterm birth rate appears to be increased)The above issues should also be discussed in a consultation about COVID-19 vaccination during pregnancy . AdditioRisk of vaccine reactogenicity, including fever (treatment with antipyretic medications such as acetaminophen decreases this risk) and dermatologic adverse effects (self-limited) Time of planned vaccination during pregnancy Extensive evidence for safety of other vaccines during pregnancyStudies favoring vaccination in pregnancy in a similar group, the rheumatology patients , 98A potential protective effect for the neonate from the placental transfer of antibodies to the fetus Risk of exposure to SARS-CoV-2 and potential for mitigation with working from home, wearing masks, and physical distancing.The above maternal and fetal risks need to be weighed against the risks of COVID-19 itself.The pregnant individual should be advised that there are no biologic reasons to believe that the vaccines currently approved are harmful to the pregnant person or fetus , 103. A 8.There is insufficient evidence regarding the continuation of IMBI therapy for dermatologic conditions in pregnant persons diagnosed with COVID-19. However, available data indicate that there is no compelling reason for treating pregnant patients differently than non-pregnant. The risks of COVID-19 vaccination in pregnant patients on IMBI therapy for dermatologic conditions can be extrapolated from experimental studies and studies in overlapping populations such as rheumatology patients. Current guidelines on COVID-19 vaccination for immunosuppressed dermatologic patients and pregnant patients separately recommend vaccination in both groups. The body of evidence indicates that mRNA COVID-19 vaccines are safe during pregnancy. Along the same lines, many biologics can be safely administered during COVID-19–some TNFαI can even benefit the course of the disease. Based on the evidence presented here, COVID-19 vaccine recommendations in pregnant patients on IBMI for dermatologic conditions should not differ from those for their non-pregnant counterparts. Collecting data for post-vaccine surveillance will help address some of the unanswered questions.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.https://www.frontiersin.org/articles/10.3389/fmed.2023.1121025/full#supplementary-materialThe Supplementary material for this article can be found online at: Click here for additional data file.Click here for additional data file.


What were the outcomes of patients hospitalized with non–COVID-19 conditions, even with negative SARS-CoV-2 test results, during the pandemic vs before the pandemic?In this cohort study of 132 240 patients hospitalized with common medical conditions, only those with heart failure or with chronic obstructive pulmonary disease or asthma exhibited a significantly higher risk-adjusted 30-day mortality during the pandemic . As COVID-19 caseloads increased, lengths of stay and risk-adjusted mortality were significantly higher for patients with COVID-19 but not for those with non–COVID-19 conditions.The findings show that most patients hospitalized with non–COVID-19 conditions (except heart failure or chronic obstructive pulmonary disease or asthma) exhibited similar risk-adjusted outcomes during the pandemic, even during COVID-19 caseload surges, suggesting resilience in the face of hospital occupancy strains. This cohort study determines whether 30-day mortality and length of stay differed in patients hospitalized for non–COVID-19 conditions before and during the pandemic. The association of inpatient COVID-19 caseloads with outcomes in patients hospitalized with non–COVID-19 conditions is unclear.To determine whether 30-day mortality and length of stay (LOS) for patients hospitalized with non–COVID-19 medical conditions differed (1) before and during the pandemic and (2) across COVID-19 caseloads.This retrospective cohort study compared patient hospitalizations between April 1, 2018, and September 30, 2019 (prepandemic), vs between April 1, 2020, and September 30, 2021 (during the pandemic), in 235 acute care hospitals in Alberta and Ontario, Canada. All adults hospitalized for heart failure (HF), chronic obstructive pulmonary disease (COPD) or asthma, urinary tract infection or urosepsis, acute coronary syndrome, or stroke were included.The monthly surge index for each hospital from April 2020 through September 2021 was used as a measure of COVID-19 caseload relative to baseline bed capacity.The primary study outcome was 30-day all-cause mortality after hospital admission for the 5 selected conditions or COVID-19 as measured by hierarchical multivariable regression models. Length of stay was the secondary outcome.Between April 2018 and September 2019, 132 240 patients  were hospitalized for the selected medical conditions as their most responsible diagnosis compared with 115 225  between April 2020 and September 2021 (114 414 [99.3%] of whom had negative SARS-CoV-2 test results). Patients admitted during the pandemic with any of the selected conditions and concomitant SARS-CoV-2 infection exhibited a much longer LOS  and greater mortality  than those without coinfection. Patients hospitalized with any of the selected conditions without concomitant SARS-CoV-2 infection had similar LOSs during the pandemic as before the pandemic, and only patients with HF  and COPD or asthma  had a higher risk-adjusted 30-day mortality during the pandemic. As hospitals experienced COVID-19 surges, LOS and risk-adjusted mortality remained stable for patients with the selected conditions but were higher in patients with COVID-19. Once capacity reached above the 99th percentile, patients’ 30-day mortality AOR was 1.80  vs when the surge index was below the 75th percentile.This cohort study found that during surges in COVID-19 caseloads, mortality rates were significantly higher only for hospitalized patients with COVID-19. However, most patients hospitalized with non–COVID-19 conditions and negative SARS-CoV-2 test results (except those with HF or with COPD or asthma) exhibited similar risk-adjusted outcomes during the pandemic as before the pandemic, even during COVID-19 caseload surges, suggesting resiliency in the event of regional or hospital-specific occupancy strains. Studies showcasing the associations of the pandemic with outcomes in patients with non–COVID-19 conditions have yielded mixed results and were limited by predominantly focusing on specific conditions , care settings , or the first wave of the pandemic.4 Furthermore, surge strain was usually measured using pandemic case counts that were not weighted for illness severity, resource needs, and hospital-specific bed constraints.Before the COVID-19 pandemic, 18 of 30 observational studies reported increased inpatient mortality during times of hospital capacity strain.2 for patients hospitalized with any of the 5 most common non–COVID-19 medical conditions requiring hospitalization: heart failure (HF), chronic obstructive pulmonary disease (COPD) or asthma, urinary tract infection (UTI) or urosepsis, ACS, or stroke.To understand the public health outcomes of caseload strain on non–COVID-19 conditions during the pandemic, we leveraged data from acute care hospitals in the single-payer universal access health care system of Canada in which all interactions with the health care system are captured. We explored the association between 30-day outcomes and an established severity-weighted metric of caseload strainSTROBE) reporting guideline.This cohort study used population-level, deterministically linked, health administrative data that were deidentified and, thus, deemed to be exempt from the need for individual patient consent by the University of Alberta Health Ethics Research Board. In Ontario, data sets were linked using unique encoded identifiers. The analysis of deidentified Ontario data was authorized under section 45 of Ontario’s Personal Health Information Protection Act. As health data privacy laws preclude the sharing of health data across provincial boundaries, the Alberta analyses were conducted within the Alberta Strategy for Patient Oriented Research Data and Research Services team, and the Ontario analyses were performed at ICES , Toronto. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  inpatient hospitalizations for similar periods before and after the COVID-19 pandemic onset  in 2 Canadian provinces . We excluded obstetric or psychiatric hospitalizations. Only the first hospitalization was included for each patient, and patients transferred between hospitals had the total hospital stay summed and attributed to the hospital in the sequence with the longest length of stay (LOS). We excluded patients who left against medical advice or were discharged to a correctional facility.International Classification of Diseases, 10th Revision (ICD-10) diagnosis code U07.1, which has sensitivity of 98%, specificity of 99%, and a positive predictive value of 92% to 93% in US and Alberta data.6 We used the Discharge Abstract Database, which captures all acute care hospitalizations and records up to 25 ICD-10–coded diagnoses and up to 20 procedure codes, to define our cohort and to build comorbidity profiles for each patient. Mortality, both in and out of the hospital, was captured from the Registered Persons Database in each province. For our analyses, we chose 5 indicator conditions accounting for the most common nondiscretionary medical case mix diagnoses in Alberta and Ontario: HF, COPD or asthma, UTI, ACS, and acute stroke.Among inpatients admitted after April 1, 2020, those with COVID-19 were identified using the COVID-19–specific 2 which captures both the quantitative and qualitative burden in each hospital-month due to COVID-19 caseload relative to baseline bed capacity. This severity-weighted index has demonstrated prognostic utility in the outcomes of patients with COVID-19.2 The monthly surge index was calculated for each hospital in Alberta and Ontario after April 1, 2020, using the following equation (where n is number of admissions for COVID-19):We used a previously published surge index,To calculate the surge index, we interrogated the Discharge Abstract Database and included admissions for patients with COVID-19; to determine the number admitted to the ICU, we included those who were admitted to a special care unit at any point during their index hospitalization (not just at baseline), even if not receiving ventilation, and identified patients requiring invasive mechanical ventilation or noninvasive positive pressure ventilation using Canadian Classification of Health Interventions procedure codes 1.GZ.31.CA and 1.GZ.31.CB, respectively. In response to the pandemic, some hospitals added acute ward and ICU beds in nontraditional spaces, and any patients admitted to these surplus areas were included in the numerator for calculating surge index but not in the denominator.We grouped the surge index into prespecified shrinking categories  to capture effects at extremes after excluding 22 (of 168) Ontario hospitals that did not admit any patients with COVID-19 during the pandemic . We did not include prepandemic data in the surge index analyses since by definition the surge index for all hospital-months before the pandemic would have been 0.The primary study outcome was 30-day all-cause mortality after admission with the 5 selected conditions or COVID-19 as the most responsible diagnosis. Length of stay was the secondary outcome. We compared outcomes (1) before vs during the pandemic for each of the conditions  and (2) across the surge index categories defined above.ICD-10 code–based case definitions for diagnoses from the index hospitalization and any hospitalizations in the 12 months prior to the index admission and weighted the Charlson Comorbidity Index score using Schneeweiss weights.9 Other nonclinical covariables included type of hospital (teaching vs nonteaching), patient residence at the time of admission , socioeconomic status quintiles , number of nonelective hospitalizations in the prior 12 months, and number of emergency department (ED) visits in the prior 6 months. All variables were prespecified and selected on the basis of potential for confounding. Risk-adjusted odds ratios (ORs) for 30-day all-cause mortality were plotted for patients with the 5 selected conditions without concomitant SARS-CoV-2 infection and for those with COVID-19 as the most responsible diagnosis across surge index categories. As some cell numbers were small, we pooled the adjusted ORs (AORs) for each province using random-effects meta-analysis using package metafor in R, version 1.4.0.10 In a sensitivity analysis, rather than examining the AOR for each of the prespecified surge index categories, we fit a logistic regression model for 30-day mortality, treating surge index as a continuous variable, and used restricted cubic splines with 4 knots at the fifth, 35th, 65th, and 95th percentiles to model the association between surge index and outcome.11 For LOS risk adjustment, we repeated the analyses using hierarchical linear models and the same covariables.We conducted analyses for each of the 5 selected conditions and COVID-19 separately . For all analyses, the patient was the unit of the analysis, and although the value of the surge index changed over time for each hospital, it was fixed for each patient since it was based on the date of the patient’s first hospitalization. We accounted for the clustering of patients within the hospital by using hierarchical (or multilevel) multivariable regression models that incorporated hospital-specific random effects to estimate the association between 30-day mortality and (1) study period (prepandemic vs pandemic) and (2) COVID-19 caseload surge category. Covariables for risk adjustment included age, sex, coronary artery disease, HF, hypertension, peripheral artery disease, ventricular arrythmias, atrial fibrillation or flutter, cancer, chronic pulmonary disease, other lung disease, dementia, diabetes, liver disease, peptic ulcer disease, kidney disease, cerebrovascular disease, and Charlson Comorbidity Index score. Race and ethnicity are not collected in routine Canadian administrative health care data and, thus, not included in the study. We used previously validated P < .05, and significance levels were not adjusted to account for multiple comparisons .All analyses were performed using SAS, version 9.4 (SAS Institute Inc), and R, version 4.0.2  statistical software. We used 2-sided tests of significance with Between April 1, 2018, and September 30, 2019, 132 240 adults  were hospitalized for a most responsible diagnosis of any of the 5 indicator medical conditions in either province, compared with 115 225  between April 1, 2020, and September 30, 2021 (114 414 [99.3%] of whom had negative SARS-CoV-2 test results) . The frePatient age, sex, and LOS were similar before and during the pandemic for hospitalizations for the 5 selected conditions . HoweverCompared with patients admitted with any of the 5 selected conditions during the pandemic, patients admitted with COVID-19 as their most responsible diagnosis were younger, more likely to be male and from urban areas or LTC facilities, had lower comorbidity burdens , were less likely to have had recent hospitalizations, and had much longer LOS, greater need for ICU admission, and higher in-hospital mortality .Compared with patients admitted in low-surge periods, those admitted with the 5 indicator conditions when hospitals were surging with higher COVID-19 caseloads were younger, had lower comorbidity scores, and had fewer prior hospitalizations; however, patients who were admitted exhibited greater need for ICU admission and ventilatory support (eTable 2 in P < .001) and more dying , but this was largely driven by the markedly poorer outcomes in the 811 patients (0.7%) with concomitant SARS-CoV-2 infection (P < .001)  . Our ana < .001) , but pat < .001) .During the pandemic, the 146 Ontario hospitals that admitted patients with COVID-19 exhibited a mean monthly surge index of 1.49 (ranging from a low of 0.12 in August 2020 to a high of 6.03 in April 2021), and the 89 Alberta hospitals exhibited a mean surge index of 1.59 (ranging from a low of 0.07 in June 2020 to a high of 7.30 in September 2021) . Examina13 We believe it is not surprising that outcomes did not appreciably change for patients with ACS or stroke, since most hospitals have expedited management pathways for these conditions that were still in force even during the pandemic.In this cohort study of patients hospitalized in Alberta and Ontario before and during the COVID-19 pandemic, we found that despite having better chronic risk factor profiles, patients admitted during the pandemic for the 5 selected conditions  exhibited poorer outcomes (more required ICU admission and more died). These findings may be due to markedly worse outcomes in the 0.7% of patients with concomitant SARS-CoV-2 infection in our cohort. However, it is important to note that patients hospitalized with HF or with COPD or asthma and without SARS-CoV-2 infection still exhibited risk-adjusted 30-day mortality rates of 16% and 41% higher than those admitted before the pandemic. While these patients may have had more severe illness when admitted to the hospital than those with the same conditions admitted before the pandemic, we did adjust for most covariables known to be associated with mortality in HF or COPD . Alternately, it is possible that patients with HF or COPD or asthma exhibited poorer outcomes during the pandemic as they were more directly competing for the same scarce mechanical ventilation resources as patients with COVID-19 compared with the other selected conditions. We do not believe that these patients with HF or COPD or asthma had undiagnosed COVID-19, as screening of all hospitalizations for SARS-CoV-2 infection became routine early in the pandemic in Alberta and Ontario.13 An alternative explanation may be a manifestation of collider bias in which disposition outcomes for LTC residents or patients with high comorbidity burdens who contracted COVID-19 may have been death prior to hospitalization or triaged in the ED to options other than acute care hospitalization.14 Regardless of the possible cause, this finding is important for public health approaches to future pandemics and for research studies of outcomes during the COVID-19 pandemic that do not include comprehensive adjustment for confounders beyond just age, sex, and Charlson Comorbidity Index scores.Our findings that patients hospitalized with a most responsible diagnosis of any of the 5 selected conditions during the pandemic were less likely to come from LTC facilities, had fewer prior ED visits or hospitalizations, and had lower comorbidity burdens suggest that LTC residents or patients with comorbidities may have been following public health advice to shelter in place and reduce their exposure risk to COVID-19. Certainly, LTC facilities instituted more stringent rules around hospital transfers and repatriation early in the pandemic in Canada.4 However, we found that outcomes were relatively stable across surge index strata for patients hospitalized during the pandemic for non–COVID-19 medical conditions. This finding is contrary to the commonly held belief, even in a survey of hospital administrators, that inpatients without COVID-19 received poorer quality of care and experienced worse outcomes during COVID-19 surges.15 Our findings suggest that the Canadian health care system may have, for the most part, weathered the storm during the pandemic or at least may have been used to running at near capacity even before the pandemic. In Canada, the average hospital occupancy rate was 92% in 2019, the highest of all Organization for Economic Co-operation and Development (OECD) countries, which is not surprising since Canada ranks 33rd of 36 OECD countries in the number of acute care beds (at 2.5 per 1000 people vs the OECD average of 4.4 per 1000 people in 2019).16 By comparison, average acute care bed occupancy in the US was 64% before the pandemic.16 However, although 30-day mortality and LOS were not significantly associated with COVID-19 caseloads, there is no doubt that the diversion of staff and resources to patients with COVID-19 has resulted in a substantial accrued care deficit in Canada (and worldwide).17Our finding that mortality risk for patients with COVID-19 was significantly associated with hospital caseloads (with higher 30-day death rates at times of surges) confirms data from other countries.18 Second, we did not have data on do-not-resuscitate status, other predesignated treatment limitations, or in-hospital or outpatient medication use. We also did not have access to clinical variables such as oxygen saturation, blood pressure, heart rate, results of blood or radiology tests, and duration of symptoms at admission to fully adjust for disease severity of the most responsible diagnoses. Third, if some patients were not tested for SARS-CoV-2, we may have misclassified them as not having COVID-19, which would have biased our findings toward the null; however, by April 2020, screening for SARS-CoV-2 infection in all patients at the time of admission was routine in both provinces.13 Fourth, we relied on administrative rather than clinical data to define comorbidities, but we did use well-validated ICD-10–based case definition algorithms. Fifth, we only examined outcomes for hospitalized patients and, thus, may have underestimated the adverse outcomes on a population basis of COVID-19 caseload surges since at-home deaths were not accounted for. In a similar vein, since we only examined outcomes for first hospitalizations for any of the selected conditions, we may have underestimated mortality outcomes, because patients hospitalized 2 or more times for the same condition in a short period have poorer outcomes. Sixth, although there appears to be a large difference between Alberta and Ontario in ICU usage for patients with the 5 selected diagnoses or COVID-19, this appears to be merely a labeling issue in what was classified as an ICU in each province by the health authorities, since the proportions of patients receiving mechanical ventilation in both provinces were relatively similar. Seventh, it should be acknowledged that the surge index number cannot be used to extrapolate the percentage of available hospital resources devoted to the care of patients with COVID-19 at any one time; rather, it was used as a metric to stratify COVID-19 caseloads (by percentile) between hospitals and across phases of the pandemic.Although we report all hospitalizations in 2 of Canada’s most populous provinces and were able to account for out-of-hospital deaths, there are some limitations to our study. First, as with any observational study, there is the possibility of bias due to unmeasured confounders, and we were unable to account for heterogeneity in management practices between hospitals and clinicians over the course of the pandemic, as well as the association of variants and vaccination.21 While surges in COVID-19 caseloads were associated with significantly higher mortality rates for patients with COVID-19, most patients hospitalized with non–COVID-19 conditions and negative SARS-CoV-2 test results (except those with HF or with COPD or asthma) exhibited similar risk-adjusted outcomes  during the pandemic, even during COVID-19 caseload surges. It is interesting to speculate to what extent these observations reflect the fact that the Canadian hospital system was used to running at near capacity even before the pandemic. Regardless, our results provide reassuring evidence of resilience in the event of future regional or hospital-specific occupancy strains .In this cohort study, hospital admissions for 5 most common most responsible diagnoses in Ontario and Alberta decreased during the first 18 months of the COVID-19 pandemic, mirroring data from other jurisdictions.


Drug treatment was recommended for stage 1 hypertensive patients (blood pressure of 130-139 / 80-89 millimetres of mercury (mmHg)) with high cardiovascular disease (CVD) risk in the 2017 Hypertension Clinical Practice Guidelines, 2018 Chinese guidelines and 2021 World Health Organization guidelines, but not in other guidelines. However, evidence on the cost-effectiveness of drug treatment among young and middle-aged patients remains scarce. This study aimed to compare the cost-effectiveness of drug treatment vs. non-drug treatment for stage 1 hypertensive patients aged <60 years with high CVD risk.A microsimulation model projected quality-adjusted life years (QALYs), health care costs, and incremental cost-effectiveness ratios for drug treatment from a societal perspective. Transition probabilities were estimated from the Kailuan study with a sample size of 34 093 patients aged <60 years with high CVD risk. Costs and health utilities were obtained from the Kailuan study, national statistics reports and published literature.Over a 15-year time horizon, the model predicted that drug treatment generated QALY of 9.36 and was associated with expected costs of 3735 US dollars ($) compared with 9.07 and $3923 produced by non-drug treatment among stage 1 hypertensive patients, resulting in a cost-saving for drug treatment. At a willingness-to-pay threshold of $10439/QALY (one gross domestic product (GDP) per capita in 2020), drug treatment had a 99.99% probability of being cost-effective for 10 000 samples of probabilistic sensitivity analysis. Sensitivity analyses by different values of transition probability, cost, utility and discount rate did not appreciably change the results. Shortening the time horizon to the average follow-up period of eight years resulted in ICER of $189/QALY for drug treatment (<1 × GDP/QALY).Our results suggested that drug treatment was a dominant strategy for stage 1 hypertensive patients aged <60 years with high CVD risk in China, which may provide evidence for policymakers and clinicians when weighing the pros and cons of drug treatment for young and middle-aged stage 1 hypertensive patients. The definition of hypertension has been a hot topic of debate over the last few years. In 2017, the American College of Cardiology/American Heart Association (ACC/AHA) published new guidelines for treatment strategies for hypertension and stage 1 hypertension was defined as a systolic/diastolic blood pressure (SBP/DBP) of 130-139 / 80-89 millimetres of mercury (mm Hg) [Recently, although individuals with SBP/DBP of 130-139 / 80-89 mm Hg were defined as non-hypertensive patients, the 2018 Chinese guidelines for the management of hypertension  and 2021Adopting new diagnostic criteria could significantly increase the prevalence of hypertension and substantially contribute to the high costs of health system. For example, the prevalence of hypertension was approximately doubled in most countries if the ACC/AHA guidelines were adopted ,7 and anHere we aimed to determine the cost-effectiveness of drug treatment vs. non-drug treatment among stage 1 hypertensive patients aged <60 years with high CVD risk from a societal perspective using data from the Kailuan study.We performed a model-based economic evaluation to assess the incremental cost-effectiveness ratio (ICER), with the outcomes expressed as cost per quality-adjusted life year (QALY) of drug treatment compared with non-drug treatment from a societal perspective for stage 1 hypertensive patients aged <60 years with high CVD risk. The ICER less than one time of per capita gross domestic product (GDP) per QALYs gained was considered as highly cost-effective . Accordi2), according to the 2018 Chinese guidelines) [We modeled the cost-effectiveness of drug treatment for stage 1 hypertensive patients in the Kailuan study, a prospective dynamic cohort study in Tangshan, China. The detailed study design of the hypertension management programme has been described previously . Brieflydelines) , those wBased on previously published models , a MarkoAs the average length of follow-up of the Kailuan study population included in this analysis was 8.23 years (range = 1.00 to 14.56 years), we simulated an eight-year time and 15-year time horizon to quantify potential benefits of drug treatment for those of young and middle-aged patients. The model cycle length was 1 year, and a half-cycle correction was applied.For transition probability, all-cause mortality and event rates for stroke and MI among stage 1 and stage 2 hypertensive patients were derived from the Kailuan study. In the Kailuan study, person-years for each participant were counted from the baseline survey until the date of death or 31 December 2020, whichever came first. The database of CVD diagnoses was obtained from the Municipal Social Insurance Institution and Hospital Discharge Register and was updated annually during the follow-up periods. All-cause mortality was linked to the municipal death registries and checked annually against local residential records, with active confirmation of survival through subdistrict offices. We used ICD-10 codes to identify CVD cases  . The recThe cost-effectiveness analyses were performed from a societal perspective and therefore both direct and indirect costs were included. These costs included hypertension screening or management costs , antihypAnnual hospitalised costs for stroke, MI, and post-stroke/post-MI were extracted from the electronic medical records in the Kailuan study and checked through the China Health Statistics Yearbook 2020 and published literature ,11. The Utility values of hypertension, stroke, MI, post-stroke, and post-MI were obtained from published literature based on the European Quality of Life-5 Dimensions Questionnaire (EQ-5D) ) age was 45.9 (11.0) years for the model population  were performed to determine how key model parameters would affect the results. First, we conducted one-way sensitivity analyses, including different values of transition probability, cost, utility, and discount rate. Second, to assess how sensitive the results were to variations in simultaneous changes of several variables, we conducted a PSA with a set of 10 000 produced results characterised by the probability distributions of outcomes resulting from the uncertainty around the input parameters. To quantify the uncertainty captured by the sensitivity, we used 10 000 Monte Carlo simulations to perform  another . Two-sidThe model predicted that drug treatment generated QALY of 9.36 and was associated with expected costs of $3735 in comparison with 9.07 and $3923 produced by non-drug treatment over a 15-year time horizon  costs of drug treatment and non-drug treatment are statistically different over 15-year time horizon with P value <0.001; the mean cost of drug treatment and non-drug treatment is $3734 (SD = $586) and $3929 (SD = $588), respectively; 2) the effectiveness of drug treatment and non-drug treatment are statistically different with P value <0.001; the mean effectiveness of drug treatment and non-drug treatment is 9.36 (SD = 0.80) and 9.07 (SD = 0.76), respectively.To our knowledge, this is the first study in the Chinese population investigating the cost-effectiveness of drug treatment vs. non-drug treatment in young and middle-aged stage 1 hypertensive patients using local incidence events and cost data. The model-based economic analysis indicated that drug treatment generated less costs from stage 2 hypertension, CVD, and productivity loss, but was more effective than non-drug treatment, suggesting that drug treatment was a dominant strategy for stage 1 hypertensive patients aged <60 years with high CVD risk over a 15-year time horizon. In addition, modeling results were robust with respect to a comprehensive sensitivity analysis.Prior studies have suggested that treatment for patients with SBP/DBP≥140/90 mm Hg was cost-effective or cost-saving, regardless of CVD risk ,28. In aNevertheless, the cost-effectiveness of drug treatment for individuals with SBP/DBP of 130-139 / 80-89 mm Hg has not been extensively examined. Using data from a cross-sectional study and published literature, Chen and colleagues  found thIn our study, drug treatment entailed additional medication use, thus the costs for stage 1 hypertension were higher in the drug treatment than in non-drug treatment. However, these costs were offset by lower costs from stage 2 hypertension, CVD and productivity loss, resulting in less total costs and cost savings. In terms of effectiveness, a recent systematic review and meta-analysis of 74 unique trials showed that drug treatment might not be associated with reduced risk of CVD and mortality at lower BP levels SBP<140 mm Hg) 0 mm Hg ,17, thus, thus17,Our findings have several public health implications. Despite the 2017 ACC/AHA guidelines would result in a substantial increase in the proportion of patients labeled as having hypertension, there might be a slight increase in the percentage of patients who are recommended drug treatment by using a combination of BP levels and CVD risk  and 2.0%Several limitations need to be acknowledged. First, our model only captured a limited number of health states, which might have underestimated the benefits of drug treatment for newly defined stage 1 hypertensive patients. Second, the recurrence rates and RR reductions were derived from published literature, in which some participants were not at a high risk of CVD. As expected, the RR reductions were greater in participants with high CVD risk compared to those with low CVD risk, resulting in underestimating QALYs and ICERs for drug treatment. Third, no robust data was available for medication adherence, so its potential impact on our results might deserve more attention. However, the potential impact of suboptimal medication adherence was likely to be mitigated by the conservative assumptions already described . Fourth,The results of the present study confirmed the hypothesis that drug treatment was cost-effective for stage I hypertensive patients aged <60 years with high CVD risk over a 15-year time horizon, as it proved lower costs from stage 2 hypertension, CVD, and productivity loss, and resulted in less total costs and cost savings. More studies are still needed to validate our results and provide more evidence for policymakers and clinicians when weighing the pros and cons of drug treatment for young and middle-aged stage 1 hypertensive patients.


It is well known that rheumatoid arthritis (RA) patients are at an increased risk of developing non-infectious pulmonary complications, especially interstitial lung disease (ILD); however, the clinician must keep in mind that lung disease could not only be a manifestation of the underlying condition, but also a consequence of using disease-modifying therapies. New-onset ILD or ILD worsening has also been reported as a possible consequence of both conventional disease-modifying antirheumatic drugs (DMARDs) and biologic agents. This study is a narrative review of the current literature regarding the potential risk of developing interstitial lung disease along with the administration of specific drugs used in controlling rheumatoid arthritis. Its purpose is to fill knowledge gaps related to this challenging patient cohort by addressing various aspects of the disease, including prevalence, disease features, treatment strategies, and patient outcomes. Drug-induced lung injury (DLI) is defined as a lung injury that specifically results from the use of a drug, including prescription and over-the-counter drugs, herbal medicines, supplements, and illegal narcotics .As causality is often difficult to prove, attributing lung injury to medication is a challenging task. The diagnosis is usually presumptive, lacking a gold standard test, and the causal connection is determined by the temporal association between drug initiation, symptom onset, radiologic abnormalities, the failure to identify a microbial agent, the absence of pre-existing lung disease, and improvement after drug discontinuation ,2.Based on these principles, the 2013 Consensus statement for the diagnosis and treatment of drug-induced lung injuries recommends the following criteria for drug-induced lung injury  Table 1Table 1.Although the exact pathogenic mechanisms of drug-induced lung injury (DLI) have not been fully understood, except for a limited number of drugs, two potential primary mechanisms have been proposed: the cytotoxic and the immune mechanisms of action. These mechanisms may be independently involved or in combination, resulting in various forms of lung injury. These two mechanisms may be influenced by contextual factors, such as smoking or underlying lung diseases  1]..1].http://www.pneumotox.com (accessed on 10 April 2023). This website is a simple, easy-to-use tool, in which, after introducing the generic name of the drug, a frequency or incidence gauge (in the form of digits within stars) indicates how many cases have been published in the literature  [Whilst the use of biologic disease-modifying agents to treat RA has led to an unprecedented improvement in clinical and functional outcomes, their safety profile remains to be fully elucidated. Almost all DMARDs are known to potentially trigger DLI in patients with RA ,5,6. A vThe treat-to-target (T2T) strategy in rheumatoid arthritis (RA) is an approach that involves setting a treatment goal (RA remission or low disease activity) based on disease activity scores . This stBy inhibiting the enzyme AICAR transformylase, Methotrexate disrupts the metabolism of adenosine and guanine, resulting in the accumulation of adenosine. The increased levels of adenosine contribute to the anti-inflammatory effects by suppressing T-cell activation, down-regulating B-cells, and enhancing the sensitivity of activated CD-95 T cells. In retrospective studies, the incidence of Methotrexate-induced lung disease has been estimated to be 3.5–7.6%, with a prevalence of 5% , and hasMethotrexate can lead to multiple respiratory problems: hypersensitivity pneumonitis, interstitial fibrosis, acute lung injury with noncardiogenic pulmonary edema, organizing pneumonia, pleuritis and pleural effusions, and pulmonary nodules with acute interstitial hypersensitivity pneumonitis being the most common ,12.Methotrexate-induced pneumonitis is reported in about 0.43% to 1% of treated patients  with a mThe risk factors for methotrexate-induced lung injury in RA patients are age (>60 years), previous DMARDs use , preexistent respiratory manifestations of RA, hypoalbuminemia, diabetes, and renal dysfunction .Sathi et al. adds as an additional risk factor for Methotrexate pneumonitis reduced baseline pulmonary function tests (PFT), advising baseline pulmonary function tests when initiating Methotrexate therapy . HoweverIn a meta-analysis of randomized controlled trials, Conway et al. demonstrated a slightly increased risk of respiratory adverse events, including ILD exacerbations in patients with RA treated with Methotrexate compared with other DMARDs and biologic agents . However, the patients treated with Methotrexate did not have an increased risk of death due to pulmonary disease [Methotrexate pneumonitis typically has an acute/subacute onset and often presents a hypersensitivity pneumonitis pattern . SeveralAllergic mechanisms are thought to cause DLI because respiratory symptoms are often accompanied by fever and peripheral eosinophilia. Drug-induced lung injury most frequently shows widespread ground glass opacity (GGO) and hypersensitivity pneumonitis-like pattern, which may resemble the imaging findings from pneumocystis pneumonia (PCP) .For a better diagnostic approach there have been developed diagnosis criteria for adverse pulmonary events associated with Methrotrexate use .The topic of chronic pulmonary injury induced by Methotrexate is highly debated: when investigating the chronic pulmonary effects of low-dose Methotrexate in RA patients (55 RA patients treated with Methotrexate and 75 RA patients in the control group), Dawson et al. did not find any evidence that Methotrexate leads to chronic pulmonary fibrosis. Moreover, in this study, it should be noted that during the 2-year follow-up, even though there was a deterioration in the pulmonary function parameters, this did not reach a significant difference .In case of Methotrexate-induced ILD, treatment consists of drug cessation and,  corticosteroids. It is not advised to reinitiate Methotrexate after an ILD-event .Leflunomide acts by inhibiting the mitochondrial enzyme dihydro-orotate dehydrogenase (DHODH) via its metabolite A771726—teriflunomide .Leflunomide-induced/exacerbated ILD first became a concern in 2004, when, months after the drug was released in Japan, post-marketing surveillance showed that sixteen patients developed de novo or exacerbated ILD, nine of whom died .There is confounding data given the fact that Leflunomide is often a second-line therapy and most patients receiving it have a Methotrexate history. A study by Suissa et al. showed that while Leflunomide use was a risk factor for developing RA-ILD, the patients at risk had either previously used Methotrexate or had a history of ILD. Moreover, the same study noticed a prescription bias: patients with preexistent ILD were twice as likely to be prescribed Leflunomide instead of Methotrexate. Therefore, in many cases, it remains difficult to demonstrate causality when suspecting Leflunomide-induced ILD . The main pathogenetic mechanism of Leflunomide-induced pneumonitis is attributed to hypersensitivity reactions .Racial factors seem to have a part in Leflunomide-induced ILD: Sawada et al. reported that, in a cohort of 5054 RA patients who were prescribed LEF, 61 patients (1.2%) developed ILD as an adverse reaction to this DMARD, which was higher than that estimated at 0.02% in Western countries . SimilarIt has been postulated that mechanisms connected to epithelial–mesenchymal transition (EMT) might be involved in Leflunomide-induced ILD . In ILD,Namba’s et al. research on Leflunomide’s metabolite, A771726, indicated that A771726 induced EMT-like characteristics in cultured human type II alveolar (A549) cells, via DHODH inhibition. A771726 treatment resulted in the upregulation of α-smooth muscle actin (α-SMA) and Col1a1 mRNA expression, and a downregulation in the expression of E-cadherin mRNA .Leflunomide-induced pneumopathy usually occurs within the first 20 weeks of therapy, being typically described as being a NSIP pattern. Risk factors associated with such lung involvement include preexisting pulmonary lesions, interstitial pneumonia, the use of a loading dose, smoking, and low body weight ,24.Sulfasalazine-induced lung disease is rather rare. A retrospective case study involving all patients in published reports between 1972–1999 treated with sulfasalazine and who had developed a possible pulmonary adverse reaction to the drug identified only 50 patients. In this cohort, there were only six patients with RA .There is currently no available data on the pulmonary toxicity of hydroxychloroquine.Whilst there have been case reports on pulmonary toxicity in azathioprine-treated patients , azathioMost bDMARDs have been linked to lung toxicity, but they have also been reported to have the potential to improve lung function and stabilize pulmonary symptoms.Regarding biological disease-modifying antirheumatic drugs (DMARDs), tumor necrosis factor (TNF) alpha inhibitors are those with the most data on drug-induced ILD.Initial concerns regarding drug-induced ILD in RA patients arose after anecdotal reports of serious exacerbations of respiratory disease following treatment with a TNF inhibitor (TNFi) in patients with pre-existing RA-ILD. Post-marketing studies have revealed that the development of ILD after TNF inhibitor therapy was a rather rare event (0.5–0.6%), but that the preexisting ILD at the moment of TNF inhibitors initiation is a risk factor for ILD exacerbations ,33,34When analyzing a RA cohort (163 patients with RA who underwent anti-TNF therapy), Nakashita et al. demonstrated a potential risk of ILD events (progression) in patients with pre-existing ILD: 24.1% of the patients with pre-existing ILD had subsequent ILD events, whilst only 3% of the patients without pre-existing ILD registered such events (still a higher proportion than the one reported by the post-marketing studies). This data, in conjunction with descriptions regarding each of the TNF alpha inhibitors, indicates that the risk of pneumonitis seems to display a class effect .In a cohort of 122 RA patients with interstitial lung disease either induced or exacerbated by TNF-targeted therapies, complete resolution was observed in up to 40% after withdrawal of the biologic agent .The data available from the British Society for Rheumatology Biologics Register showed that the survival of RA-ILD patients is not influenced by anti-TNF-α therapy .The imaging pattern in TNF-inhibitors-induced ILD is variable with different patterns of interstitial involvement, most commonly UIP or NSIP; cases of organizing pneumonia, diffuse alveolar damage, and lymphoid interstitial pneumonia have also been described .It should also be noted that patients with RA initiated on TNF inhibitors often continue conventional DMARD therapy. In patients with concomitant Methotrexate therapy, an increased frequency of development of Methotrexate pneumonitis has been suggested . Regarding the relationship between specific biological medication and drug-induced ILD, post-marketing surveillance of infliximab’s safety profile in 5000 Japanese RA patients identified ILD in 25 patients (0.5%), after a mean of 2.8 infusions of infliximab, with a mean number of days from the first infusion to ILD diagnosis of 76.8 days (36–153 days) .Similar data exist regarding Adalimumab: the data published by the Japan College of Rheumatology, on 3000 RA patients treated with adalimumab, reported the occurrence of interstitial pneumonia in 0.6% of patients. Additional post-marketing surveillance data on a cohort of 7440 patients placed the prevalence of ILD among adalimumab-treated patients at 0.5% ,40.Etanercept (ETN) was studied in a randomized controlled trial in the treatment of idiopathic pulmonary fibrosis, which showed no significant differences observed in the efficacy endpoints between the placebo and active treatment groups .The post-marketing surveillance of etanercept in RA treatment, conducted by JCR (the Japan College of Rheumatology), revealed 0.6% of study patients developed ILD ,42.As to the impact of etanercept in combination with DMARDs, not only did the concomitant use of etanercept and methotrexate show a better RA control, but also significantly lower incidence rates for total adverse events, including ILD (when compared to etanercept as a monotherapy or associated with other DMARDs) Certolizumab, similarly to other TNFα inhibitors, may lead to acute exacerbations in RA-ILD patients, probably via NLRP3 inflammasome activation precipitate pneumonitis. The first case was reported in 2013 by Glaspole et al. ,45 and fThere is even less data regarding alternate mechanisms of action (MOAs) agents: T-cell, B-cell, and interleukin-6 inhibitors. A study by Curtis et al., evaluating ILD incidence and exacerbation among RA patients treated with MOAs  compared with anti-TNFα agents, showed no significant differences regarding the risk of ILD and its related complications. It should be also noted that the patients in the MOAs group were more likely to have prior exposure to other drugs; for instance, prior biologic exposure and corticosteroid use was highest in patients in the tocilizumab and rituximab groups .Rituximab seems to be a relatively safe therapy in RA patients with lung involvement. Given the fact that a worsening of preexisting ILD in RA patients treated with TNF inhibitors has been reported in the literature, Rituximab has often been the biological agent of choice in these cases. Even though data available on the matter are still rather scarce, several studies have seemed to suggest that Rituximab has a better safety profile in RA-ILD patients In a cohort of 264 patients with RA that had received RTX, out of which 38 patients (14%) had lung involvement, lung disease remained clinically and radiologically stable in most patients, with just a single patient showing slow progression of the disease over 4 years of follow-up .A cohort study involving 53 RA patients with preexisting ILD suggests that, at the very least, patients with stable ILD remain stable in regards to pulmonary function after the initiation of Rituximab therapy during prolonged follow-up .Another small-scale study, which did not specifically focus on RA patients but rather on patients with ILD that did not respond to conventional immunosuppression, followed 44 patients initiated on Rituximab for a period of two years. The results of this study seem to indicate that Rituximab treatment is associated with a reduction in FVC and DLCO decline, especially when used in patients with connective-tissue-disease-associated ILD .Similar results were published by Franzen et al. In a cohort of 33 RA patients treated with Rituximab, when evaluated with serial pulmonary function tests, while no instances of respiratory symptoms were reported, the DLCO showed a progressive decline during follow-up with a maximum reduction of 6.1% at 26 weeks (when compared to baseline). The risk factors for pulmonary function changes post-rituximab were cigarette smoking, repeated administration of the drug, and corticosteroid use (prednisone). The gradual decrease in DLCO suggests the possibility of subclinical pulmonary toxicity induced by rituximab, but it should be noted that both steroid use and repeated courses of rituximab are linked to a more severe RA .In regards to patient mortality, the data from the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) suggest that the RA-ILD who were administered rituximab as their initial biologic had superior long-term survival rates when compared to those who began treatment with TNF inhibitors, with an adjusted 5-year risk of mortality in the RTX-treated patients of approximately half that in the TNF inhibitor-treated patients, but the difference was not statistically significant  .At the time of this review, the data on the impact of Abatacept in patients with RA-ILD are reassuring. A multicenter study including 263 RA-ILD patients treated with Abatacept showed an improvement or stabilization after 1 year of therapy regarding dyspnea scores (in 91.9%), FVC (in 87.7%), DLCO (in 90.6%), and chest HRCT (in 76.6%) .A prospective study on a cohort of 57 RA-ILD patients treated with abatacept for a median (IQR) of 27.3 (12.2–42.8) months demonstrated both arthritis control and pulmonary involvement stabilization in 71% of patients. The factors associated with lung disease progression and mortality were high disease activity  and low baseline DLCO and FVC values .In another cohort of 44 patients with RA-ILD treated with Abatacept, only 11.4% experienced a significant worsening during the 18-month follow-up period . The variables associated with RA-ILD worsening were current smoker status and concomitant Methotrexate use . Another study that compared the effect of biological therapies on airway and interstitial lung disease in RA patients found abatacept to be an independent protective factor for both RA-ILD, but also for airway disease exacerbation . When comparing the safety of Abatacept in monotherapy with ABA associated with synthetic DMARDs in RA patients with interstitial lung disease, both strategies seem to have similar safety and effectiveness profiles. In a retrospective multicenter study of RA-ILD Caucasian patients treated with abatacept either as monotherapy associated with Methotrexate or non-Methotrexate DMARDs, more than 70% (out of 263) of the patients had stable or improved ILD after 18 months of treatment, with no significant differences between treatment groups .p = 0.019), suggesting that the acute exacerbations of RA-ILD were likely attributable to uncontrolled disease activity rather than an adverse effect of the drug [There are data suggesting that uncontrolled arthritis activity during tocilizumab treatment could lead to an acute exacerbation of RA-ILD. A retrospective, case-controlled study involved 395 consecutive RA patients treated with tocilizumab, 78 with ILD, and 317 without ILD. Six acute exacerbations occurred, after a median treatment duration of 48 weeks. The patients experiencing acute ILD exacerbations had higher disease activity measured using the Clinical Disease Activity Index (CDAI) at 24 weeks , 38  were reported to have interstitial lung disease (ILD), with 22 of them having either a concurrent or prior medical history of ILD at the beginning of the study. It should be noted also that 24 of the ILD patients had a prior history of biological DMARDs. Multivariate logistic regression analysis identified advanced age (≥65 years) and previous or concurrent ILD at baseline as the risk factors for ILD .In a study that included 125 elderly (>65 years) patients with RA treated either with Abatacept (n = 47) or Tocilizumab (n = 78), the most common adverse event that resulted in the discontinuation of Tocilizumab treatment was ILD. Out of the five patients who developed ILD while on Tocilizumab, two had a worsening of pre-existing ILD, while four had been concurrently using Methotrexate. In contrast, ILD was not reported as an adverse event leading to the discontinuation of abatacept in elderly patients with RA .In a cohort of 11,219 patients, totaling 13,795 episodes of biologic exposure, there were no significant differences in the risk of ILD and its related complications between RA patients receiving different classes of biological therapy. The data suggests that the incidence and exacerbation of ILD in the Tocilizumab and Rituximab groups may be exaggerated by treatment resistance or by the severity of the disease, since the first line of biologics were anti-TNF agents in most patients .Information regarding anakinra’s pulmonary effects in RA patients is scarce, and so far, there have not been any randomized controlled trials in regard to RA-ILD. The data scarcity may be because anakinra use has seen a significant decline over time. The newer therapeutic options seem to provide better RA control, a better safety profile, and more convenient dosing options.Regarding targeted-synthetic DMARDs, which represent a somewhat newer alternative in RA treatment, information pertaining to interstitial lung disease and pulmonary safety is currently limited, but the results published thus far seem to indicate a low rate of ILD development during Janus-kinase inhibitor use ,62,63.Moreover, there is data regarding Tofacitinib: a post hoc analysis of 21 trials, including 7061 patients  who received tofacitinib, showed that the IR for an ILD event was 0.18 for both tofacitinib 5 mg BID and 10 mg BID, an incidence associated with known risk factors of RA-ILD, such as age, smoker status, and high disease activity (DAS28 scores) .A retrospective study using claims data pertaining to 28,559 patients with RA from the Optum Clinformatics Data Mart Database showed that, when calculating the IRs per 1000 person-years for ILD, patients who received tofacitinib were 69% less likely to develop ILD (IR = 1.48) compared to those treated with adalimumab (IR = 4.30) .p  <  0.001) [In a retrospective study of 75 patients with RA and ILD treated either with Janus kinase inhibitors (tofacitinib 5 mg BID or baricitinib 4 mg daily) or abatacept (125 mg/week) for at least 18 months, the data showed similar safety profiles in regard to pulmonary outcomes. RA-ILD stability or improvement was reached in 83.9% and 88.6% of patients, respectively. In the multivariate regression analysis, the only variable related to RA-ILD deterioration in patients treated with Janus kinase inhibitors was disease duration (  0.001) .In a descriptive, multicentric, retrospective cohort study that included data pooled from eight randomized trials, with 3770 RA patients treated with baricitinib, with 12,358 patient-years of exposure, Salvarani et al. identified 21 ILD cases with an exposure-adjusted incidence rate (EAIR) of 0.17 per 100 patient-years of exposure (PYE), proving a low risk of developing ILD during treatment .Furthermore, in a retrospective exploratory study that analyzed a cohort of 43 RA-ILD patients treated with either baricitinib (65.12%), tofacitinib (20.93%), filgotinib (6.98%), or upadacitinib (6.98%), the DLCO improved or remained stable in 80% of the cases. The forced vital capacity followed the same trend, as it worsened in only 10.71% of the patients and the chest HRCT demonstrated a progression of ILD in 9.30%. While combined therapy with methotrexate was documented in 38.10% of the patients, no improvement or deterioration was seen in the HRCT and pulmonary function tests between those with monotherapy or those with concomitant methotrexate use . These results suggest that treatment with Janus kinase inhibitors may provide benefit in reducing the risk of developing RA-ILD. The establishment of treatment guidelines for RA-ILD continues to present an ongoing challenge, with further complications arising from the potential pulmonary toxicity of both synthetic and biologic DMARDs. Our review will hopefully be able to aid the clinician in choosing the optimal treatment strategy for both at-risk patients and those with established ILD.Both initial and subsequent evaluations of RA patients should consider both articular and extraarticular manifestations. Risk factors , clinical findings, dyspnea scales, the 6-min walk test, pulmonary function tests (PFT), DLCO, and imaging findings should be documented in order to assess the severity of pulmonary involvement and to detect its progression.Routine clinical evaluations of RA patients should include pulmonary evaluation, with an emphasis on a structured follow-up plan for individuals with identified ILD or those at high risk, including regular clinical evaluations, PFTs, and imaging assessment.Optimizing therapy and follow-up strategies require a multidisciplinary approach that involves, at a minimum, a rheumatologist, a pulmonologist, and a radiologist. Drug-induced lung damage should also be considered in any RA patient who develops respiratory symptoms or new imaging changes during therapy.In patients with low disease activity/remission and with stable pulmonary involvement, the ongoing therapy should be continued; however, in patients with progressive ILD and active joint disease, switching to JAK inhibitors or alternate mechanisms of action (MOAs) agents could be beneficial.During the past two decades, we have witnessed many exciting developments in the treatment of rheumatoid arthritis. While this is very encouraging, ongoing research regarding the long-term safety profile of these agents is essential, especially among patients with extra-articular manifestations such as RA-ILD, or patients with preexisting pulmonary conditions. Moreover, there is a need for clinical registries/randomized controlled trials on antifibrotic agents and DMARD associations.


A total of 14/32 (43.8%) patients reported normal preoperative ejaculatory function in the EUS-RASP group, and 11/14 (78.6%) maintained antegrade ejaculation postoperatively. Conclusions: Extraperitoneal urethra-sparing RASP is an effective and feasible procedure that can improve voiding function and allow for the maintenance of ejaculatory function in patients with large prostates.Background: We report a comparative analysis of extraperitoneal urethra-sparing robot-assisted simple prostatectomy (EUS-RASP) versus robot-assisted simple prostatectomy (RASP) using the Freyer approach for patients with a large prostate volume greater than 80 mL. Methods: A total of 32 patients underwent EUS-RASP, and 30 underwent RASP from April 2018 to November 2021. All the perioperative data and 6-month follow-up data were collected prospectively. We retrospectively evaluated baseline characteristics and functional outcomes, including International Prostate Symptom Scores (IPSSs) and quality of life (QOL), maximum flow rate, and post-void residual volume, between the two groups. Sexual function was analyzed in the EUS-RASP group. Results: The patients undergoing EUS-RASP and RASP had comparable baseline characteristics and functional outcomes. The EUS-RASP group showed a shorter operative time (123.4 ± 15.2 min vs. 133.7 ± 21.4 min,  Robot-assisted simple prostatectomy (RASP) was first introduced in 2008, during the widespread introduction of robotic techniques into urological surgery . DiffereWe considered the urethra-sparing RASP (US-RASP) approach as a promising solution among several attempts to address these concerns. Due to technical challenges in urethra-sparing prostatectomy, US-RASP has been attempted relatively recently, but only a few studies have been reported ,12,13,14This study was a retrospective review of data prospectively collected into an Institutional Review Board (IRB)-approved registry database . Consecutive patients with large BPH (>80 mL) underwent EUS-RASP and RASP (Freyer approach) from April 2018 to November 2021. All the perioperative and functional data and at least 6 months of follow-up data were collected prospectively. The primary purpose of this study was to introduce our EUS-RASP technique and evaluate its perioperative and functional outcomes.The inclusion criteria were (1) patients with BPH of more than 80 mL measured by transrectal ultrasound (TRUS) and the failure of medical treatment and (2) those with the ability to understand the details of a validated questionnaire, including the International Prostate Symptom Score (IPSS). The IPSS  was administered to all the patients preoperatively and 6 months postoperatively. Sexual function was assessed in the EUS-RASP cohorts before surgery and 6 months postoperatively using the International Index of Erectile Function-5 (IIEF-5) and the Male Sexual Health Questionnaire-Ejaculation Dysfunction-Short Form (MSHQ-EjD-SF).In all cases, multiparametric magnetic resonance imaging (mpMRI) was performed to evaluate anatomical structures in the pelvic cavity and for prostate cancer screening before surgery. In the cases with high prostate-specific antigen levels , abnormal digital rectal examination, or definite focal mass lesion suggestive of malignancy in the prostate gland on mpMRI or TRUS, the patients underwent a TRUS-guided or target biopsy to exclude the presence of prostate cancer. Patients with a median prostate lobe were excluded from the EUS-RASP group. A single experienced urologist performed the EUS-RASP for 32 patients. Another experienced urologist performed a Freyer procedure RASP for 30 patients.All the EUS-RASPs and RASPs were performed using a da Vinci Xi Surgical System  with a four-arm configuration.(1) Preparation for robot docking via the extraperitoneal approach and technique to place trocarsUnder general anesthesia, the patient was placed in the Trendelendurg position (about 10–15 degrees) in a supine state. Sliding was prevented by the placement of shoulder support. An indwelling urethral catheter  was inserted after sterilizing the surgical site and preparing the surgical instruments. After making a 3 cm vertical incision 1.5–2 cm below the umbilicus, subcutaneous tissues and Scarpa’s fascia were dissected. After the right rectus sheath was incised longitudinally, the rectus abdominis muscle and the peritoneum were bluntly separated with a finger while the rectus muscle was pushed laterally. When adequate space was created, the preperitoneal distention balloon system  was inserted toward the symphysis, and the balloon was fully inflated 2 or 3 times to secure the extraperitoneal surgical space as much as possible. After removing the PDB balloon system, a glove port  was inserted. Confirming that it was sealed, gas was injected to form a pneumopreperitoneum. The robot camera port was placed in the midline incision area with the peritoneum uninjured. The remaining robot trocars and an assistant port (three 8-mm robot instruments and one 10-mm trocar for assistance) were placed, as shown in (2) Urethra-sparing adenoma enucleation method in the retropubic spaceAfter exposing the prostatic capsule by removing pre-prostatic fat from the retropubic space, a transversal incision was made halfway between the bladder neck and the dorsal venous complex B. The cl(3) Removing concomitant bladder stonesIf bladder stones were present, they were removed after prostatic adenoma removal. After opening the anterior wall of the bladder longitudinally, the stones were removed from the bladder and placed in the surgical bag with the prostate adenoma. The bladder incision was closed with watertight 3-0 absorbable sutures. Finally, the bladder was filled with 150 cc of saline to check for leaks. In the case of a concomitant bladder stone, the indwelling urethral catheter was removed on the fifth day after surgery.The technique has been described in detail in a previous paper  and is bThe initial clinical workup data, including detailed history-taking and physical examination, age, body mass index (BMI), American Society of Anesthesiologists (ASA) score, laboratory tests, and prostate volume measured by TRUS, were gathered. All the patients underwent IPSS and QOL evaluations and measurements of PSA levels, maximal urinary flow rate (Qmax), and post-void residual volume (PVR) preoperatively and 6 months postoperatively. Other postoperative data included operative time, pathological adenoma weight, the presence of CBI, CBI duration, time to urethral catheter removal, time to drain removal, and length of stay. Postoperative complications were assessed according to the Clavien–Dindo classification system . After surgery, a 22 Fr 3-way Foley catheter was placed, and CBI was performed in the RASP patients. CBI was not performed in the EUS-RASP group, and the Foley catheter was removed the day before or on the day of discharge. If significant hematuria persists, CBI is prolonged. The Foley catheter was removed on the seventh day after discharge in the RASP group or on the day of discharge only for patients hospitalized for about one week. Prophylactic antibiotics with second-generation cephalosporins were administered from the day of surgery to the first postoperative day. Both groups were encouraged to ambulate early.t-test. Statistical significance was indicated by a two-sided p-value of < 0.05. All the statistical tests were performed with the Statistical Package of Social Science for Windows , version 22.0.The categorical variables are reported as frequencies and percentages using the chi-squared and Fisher’s exact tests. The continuous variables are reported as the means with standard deviation using the Student’s p = 0.446) were not significantly different. The patient characteristics and BPH-related complications are summarized in p = 0.034). The amount of estimated blood loss, blood transfusion rate, and change in serum hemoglobin levels were not significantly different between the groups. Both groups showed a similar resected adenoma weight , postoperative PSA levels , and follow-up duration . The time to Foley catheter removal  and length of hospital stay  were significantly longer in the RASP group where CBI was not performed. No patient in the EUS-RASP group reported urinary incontinence, whereas one (3.3%) patient in the RASP group did. There was no postoperative urethral stricture in either group. In the EUS-RASP group, four cases with a wide-opened urethra injury on both sides were converted to conventional RASP and were excluded from the study. Six  cases of minimal urethral tearing were sutured with 4-0 monofilament stitches. Complete urethra-sparing simple prostatectomy without any urethral tearing was performed in 26/32 cases (81.3%). p = 0.728). In the EUS-RASP cohort, one (3.1%) patient experienced wound infection (grade 1), and three (10.0%) patients had grade 2 postoperative complications . In the RASP cohort, three (10.0%) patients had grade 2 postoperative complications , and two patients experienced grade 3a postoperative complications ). One patient who experienced RIH had anal pain after urination for several days postoperatively. There was no significant difference in the rate of postoperative complications , IPSS-QOL , Qmax , or PVR  showed no statistically significant differences between the two groups. At the 6-month follow-up, there were significant improvements in the IPSSs , IPSS-QOL , Qmax , and PVR  in the two groups. The pre- and postoperative functional outcomes are presented in In the EUS-RASP group, 18 patients  were sexually active (IIEF-5 > 17), and 14 of those patients  had normal ejaculatory function preoperatively. All the sexually active patients maintained sexual potency postoperatively . Eleven  of fourteen patients with normal ejaculatory function showed normal ejaculatory function after surgery . In the six cases of minimal urethral tearing, ejaculatory function was maintained in two of the three patients (66.7%) who had normal ejaculatory function preoperatively. In contrast, in the case of no urethral tearing, the maintenance rate of ejaculatory function at 6 months after surgery was 81.8% .The potential benefits of US-RASP make it a worthwhile option for improving the quality of life of sexually active men. Although the exact mechanisms of ejaculation dysfunction after BPH surgery are still unclear, the urethra-sparing prostatectomy technique can preserve ejaculatory function and anatomical structures, such as the prostatic urethra, bladder neck, and ejaculatory duct ,14,16. HThe US-RASP via an extraperitoneal approach was first described in a study by Wang and co-workers . They peAnother US-RASP study via a transperitoneal approach has suggested that the use of near-infrared fluorescence imaging in US-RASP can improve the identification and preservation of the prostatic urethra . AlthougWe compared and analyzed US-RASP (Madigan technique) and a nonurethra-sparing technique (Freyer approach). Both groups showed significant improvements in voiding function before and after surgery without statistical difference. The longer time until Foley catheter removal and length of hospital stay in the RASP group using the Freyer technique was likely due to the need for postoperative CBI. In the EUS-RASP group, the Foley catheter was quickly removed because CBI was not performed, which is considered to have shortened the hospitalization period. In the EUS-RASP group, manual irrigation was performed to check for intravesical clots in five patients with slightly pinkish urine, but CBI was not necessary. Compared to RASP, EUS-RASP preserves the urethra and bladder neck without damaging the bladder, resulting in almost no postoperative hematuria. This eliminates the need for CBI and shortens Foley catheterization, leading to less perioperative morbidity and good functional results. The urethra sparing itself using the robotic platform is sufficiently reproducible by the extraperitoneal approach, which also contributes to a rapid recovery. The most important advantage of EUS-RASP is that it allows for a high preservation rate of postoperative ejaculation.Our study had the advantage of comparing RASP using the Freyer procedure and EUS-RASP but had several limitations. The limitations included the retrospective study design, a small sample size, and a short follow-up period. Since patients with a median lobe were excluded from the EUS-RASP group, they should be included in future studies. The failure to compare the recovery rates of voiding function and sexual function through longer follow-ups should be addressed in future studies. Nevertheless, our study has significance as a comparative study of EUS-RASP that has been under-reported to date. This study also has significance in explaining the advantages of the EUS technique. Thus, an important option in preoperative counseling for young and sexually active men with large BPH who require surgical treatment was presented.EUS-RASP is a reproducible, effective, and safe surgical method compared to the existing RASP method. This technique obviated the need for postoperative CBI and shortened the time until Foley catheter removal and the hospitalization days. The introduction of this technique is expected to play an important role in improving the quality of life of sexually active male patients with large BPH by preserving ejaculation function.