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Here, we expound on the view that Xist RNA directly controls Polycomb repressive complex 2 (PRC2) recruitment, off-loading to chromatin, catalytic activity, and eviction from chromatin. RNA-PRC2 interactions also control RNA polymerase II transcription pausing. Dynamic RNA folding determines PRC2 activity. Disparate studies and interpretations abound but can be reconciled., Competing Interests: Declaration of interests J.T.L. is an advisor to Skyhawk Therapeutics, a co-founder of Fulcrum Therapeutics, and a Non-Executive Director of the GSK. To the author’s knowledge, none of these entities work in the subject area covered by this commentary., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Osteoporotic vertebral compression fractures (OVCF) significantly contribute to increased morbidity and mortality in aging populations. When adjusted for age, South Korea has the highest global prevalence of OVCF, with rates of 544 per 100,000 men and 1,575 per 100,000 women. Moreover, patients with OVCF are at a heightened risk of additional fractures, with the risk of new vertebral fractures being up to 5-fold higher. Therefore, in treating patients with OVCF, it is essential to address the current symptoms and take preventive measures against further fractures. Although pharmacological treatment is crucial, it may be insufficient for all patients with OVCF, with more severe cases often requiring physical therapy or surgical intervention. This review aimed to explore effective physical therapy methods for patients with OVCF and summarize surgical techniques for high-risk older patients with various underlying conditions., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2024 Korean Neurotraumatology Society.)

Using halo-tagged PRC2 and "CLAP" methodology, Guo et al. recently came to the conclusion that PRC2 is not an RNA binding protein (RBP). They suggested that previous findings are CLIP artifacts and argue that RNA cannot play a direct role in PRC2 regulation. Here, we perform a re-analysis of the authors' raw datasets and come to contrary conclusions. First, CLAP demonstrates significant PRC2 enrichment throughout the transcriptome, including in XIST's Repeat A (RepA) motif. Second, our re-analysis of the authors' CLAP and CLIP datasets demonstrates that the two methods yield similar outcomes, with both showing PRC2 enrichment in the transcriptome. Furthermore, PRC2 demonstrates more RNA binding peaks than SAF-A and PTBP1. Additionally, re-analysis of CLAP contradicts the authors' conclusion that CTCF and YY1 are not RBP. The discrepancies may be attributable to the authors' unconventional data normalization, methods of determining significance, and lack of minus-tag and input controls in some experiments.

Vascular Ehlers-Danlos Syndrome (vEDS) is an inherited connective tissue disorder caused by COL3A1 gene, mutations that encodes type III collagen, a crucial component of blood vessels. vEDS can be life-threatening as these patients can have severe internal bleeding due to arterial rupture. Here, we generated induced pluripotent stem cell (iPSC) lines from two vEDS patients carrying a missense mutation in the COL3A1 (c.226A > G, p.Asn76Asp) gene. These lines exhibited typical iPSC characteristics including morphology, expression of pluripotency markers, and could differentiate to all three germ layer. These iPSC lines can serve as valuable tools for elucidating the pathophysiology underlying vEDS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The 22-question SinoNasal Outcome Test (SNOT-22) assesses chronic rhinosinusitis (CRS) severity. We aimed to identify predictors of SNOT-22 score improvement following highly effective modulator therapy (HEMT) initiation and to corroborate the SNOT-22 minimal clinically important difference (MCID) in adults with cystic fibrosis (CF)., Methods: Prospective observational data was pooled from four studies across 10 US centers investigating people with CF (PwCF) and CRS. Three studies evaluated HEMT's impact on CRS. For participants enrolled prior to HEMT initiation, SNOT-22 scores were obtained at baseline and after 3-6 months of HEMT. Multivariate regression identified predictors of improvement. Cronbach's alpha and four distribution-based methods were used to assess internal consistency and calculate the MCID of the SNOT-22., Results: A total of 184 PwCF participated with mean baseline SNOT-22 scores ranging from 18.1 to 56.7. Cronbach's alpha was ≥0.90 across sites. Participants at sites with pre- and post-HEMT data reported improvement in SNOT-22 scores after initiating HEMT (all p < 0.05). Worse baseline SNOT-22 score (odds ratio (OR): 1.05, p < 0.001, 95% CI: 1.02-1.08), F508del homozygosity (OR: 4.30, p = 0.040, 95% CI: 1.14-18.99), and absence of prior modulator therapy (OR: 4.99, p = 0.017, 95% CI: 1.39-20.11) were associated with greater SNOT-22 improvement. The mean MCID calculated via distribution-based methods was 8.5., Conclusion: Worse baseline sinonasal symptoms, F508del homozygosity, and absence of prior modulator therapy predicted greater improvement after HEMT initiation. The mean MCID for SNOT-22 in PwCF is 8.5 points, similar to non-CF individuals with CRS, and provides a threshold specifically for PwCF. The SNOT-22 has strong internal consistency in PwCF., Level of Evidence: 3 Laryngoscope, 134:3965-3973, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Treatment approach to type A aortic dissection with malperfusion, immediate open aortic repair vs upfront endovascular treatment, remains controversial. From January 2017 to July 2021, 301 consecutive type A repairs were evaluated at our institution. Starting in 2019, all type A aortic dissections were performed in a fixed-fluoroscopy, hybrid operating room. Propensity score matching was used to control baseline patient characteristics between traditional and hybrid operating room approaches. There were 144 patients in the traditional group and 157 in the hybrid group. In the hybrid group, 41% (64/157) underwent intraoperative angiograms, and of those, 58% (37/64) received at least 1 endovascular intervention. Following propensity matching, 125 patients remained in each the traditional and hybrid groups. Thirty-day survival was significantly improved in the hybrid cohort at 96.7% (122/125) as compared to the traditional cohort at 87.2% (109/125) (P = 0.002). There were no significant differences in perioperative paralysis (1.6% vs 1.6%, P > 0.9), new hemodialysis (12% vs 9.6%, P = 0.5), fasciotomy (2.4% vs 5.6%, P = 0.20, and exploratory laparotomy (1.6% vs 4.8%, P = 0.3). The hybrid operating room approach to type A aortic dissection, provides the ability to immediately assess distal malperfusion and perform endovascular interventions at the time of open aortic repair, and is associated with significantly higher 30-day and 2-year survival when compared to a stepwise repair approach in a traditional operating room., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Selective neurectomy or muscle resection techniques for calf reduction conventionally focus on the gastrocnemius muscle. However, the underlying soleus muscle plays an important role in muscular calf hypertrophy. In the authors' experience, the results of calf reduction have been suboptimal in patients with severe muscular calf hypertrophy who underwent gastrocnemius muscle resection only. This article describes a new calf reduction method that uses concurrent gastrocnemius muscle resection and soleus muscle neurectomy using an endoscope-assisted single-incision approach in patients with severe muscular calf hypertrophy., Methods: A total of 139 patients who underwent simultaneous gastrocnemius muscle resection and soleus muscle neurectomy for severe calf hypertrophy from March of 2017 to June of 2020 were retrospectively analyzed., Results: After combined gastrocnemius resection (mean weight per calf, 349 g) and soleus neurectomy, about 3.8 to 8.2 cm (mean, 6.4 cm) or 12.8% to 24.3% (mean, 16.6%) of the calf was reduced. Complications included cellulitis, hematoma, seroma, and mild depression ( n = 1 each). Two patients had traction injury to the sural nerve. One patient developed Achilles tendon rupture at 2 months postoperatively. No patient complained of functional impairment with respect to easy fatigability, stability, gait, or sport activities at 6 months postoperatively., Conclusion: This study is the first to combine gastrocnemius muscle resection with selective soleus muscle neurectomy to achieve the most efficient calf reduction for severe muscular calf hypertrophy., Clinical Question/level of Evidence: Therapeutic, IV., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Objective: The outcomes of carotid revascularization in patients with prior carotid artery stenting (CAS) remain understudied. Prior research has not reported the outcomes after transcarotid artery revascularization (TCAR) in patients with previous CAS. In this study, we compared the peri-operative outcomes of TCAR, transfemoral CAS (tfCAS) and carotid endarterectomy (CEA) in patients with prior ipsilateral CAS using the Vascular Quality Iniatitive., Methods: Using Vascular Quality Initiative data from 2016 to 2023, we identified patients who underwent TCAR, tfCAS, or CEA after prior ipsilateral CAS. We included covariates such as age, race, sex, body mass index, comorbidities (hypertension, diabetes, prior coronary artery disease, prior coronary artery bypass grafting/percutaneous coronary intervention, congestive heart failure, renal dysfunction, smoking, chronic obstructive pulmonary disease, and anemia), symptom status, urgency, ipsilateral stenosis, and contralateral occlusion into a regression model to compute propensity scores for treatment assignment. We then used the propensity scores for inverse probability weighting and weighted logistic regression to compare in-hospital stroke, in-hospital death, stroke/death, postoperative myocardial infarction (MI), stroke/death/MI, 30-day mortality, and cranial nerve injury (CNI) after TCAR, tfCAS, and CEA. We also analyzed trends in the proportions of patients undergoing the three revascularization procedures over time using Cochrane-Armitage trend testing., Results: We identified 2137 patients undergoing revascularization after prior ipsilateral carotid stenting: 668 TCAR patients (31%), 1128 tfCAS patients (53%), and 341 CEA patients (16%). In asymptomatic patients, TCAR was associated with a lower yet not statistically significant in-hospital stroke/death than tfCAS (TCAR vs tfCAS: 0.7% vs 2.0%; adjusted odds ratio [aOR], 0.33; 95% confidence interval [CI], 0.11-1.05; P = .06), and similar odds of stroke/death with CEA (TCAR vs CEA: 0.7% vs 0.9%; aOR, 0.80; 95% CI, 0.16-3.98; P = .8). Compared with CEA, TCAR was associated with lower odds of postoperative MI (0.1% vs 14%; aOR, 0.02; 95% CI, 0.00-0.10; P < .001), stroke/death/MI (0.8% vs 15%; aOR, 0.05; 95% CI, 0.01-0.25; P < .001), and CNI (0.1% vs 3.8%; aOR, 0.04; 95% CI, 0.00-0.30; P = .002) in this patient population. In symptomatic patients, TCAR had an unacceptably elevated in-hospital stroke/death rate of 5.1%, with lower rates of CNI than CEA. We also found an increasing trend in the proportion of patients undergoing TCAR following prior ipsilateral carotid stenting (2016 to 2023: 14% to 41%), with a relative decrease in proportions of tfCAS (61% to 45%) and CEA (25% to 14%) (P < .001)., Conclusions: In asymptomatic patients with prior ipsilateral CAS, TCAR was associated with lower odds of in-hospital stroke/death compared with tfCAS, with comparable stroke/death but lower postoperative MI and CNI rates compared with CEA. In symptomatic patients, TCAR was associated with unacceptably higher in-hospital stroke/death rates. In line with the postprocedure outcomes, there has been a steady increase in the proportion of patients with prior ipsilateral stenting undergoing TCAR over time., Competing Interests: Disclosures None., (Copyright © 2024. Published by Elsevier Inc.)

REBa 2 Cu 3 O 7 - x (REBCO, RE = rare earth)-coated conductor is a competitive option in terms of current-carrying capacity and high-stress durability in developing high-field magnets for nuclear magnetic resonance (NMR) research. Meanwhile, a technical challenge in utilizing a stand-alone REBCO NMR magnet is an unexpected difference in the field uniformity between the designed and measured values after being constructed and charged, i.e., harmonic errors. Bortot et al., and Li et al., reported analytic evidence of the related issue. However, sufficient research has not yet been conducted, so evidence should be supplemented further. Here we report harmonic errors due to screening current and inconsistent conductor thickness, confirmed by a 400 MHz 1 H NMR magnet development project. The magnet was first charged up to its operating current, and then multiple overcharge-discharge cycles were applied, which was an empirically optimized operation protocol. A field mapping device obtained magnetic fields at designated locations in the room-temperature bore. The result showed over 100 ppm field uniformity difference between designed and measured values. A simulation model was developed considering screening current and inconsistent conductor thickness for reproducing the field distribution. Comparison of voltages and fields between simulation and measurement validated the model. Further analysis of the overcharge-discharge effect on harmonic errors demonstrated that even and odd-order harmonics are mainly attributed to screening current and geometric inconsistency while confirming the limitation of the screening current mitigation effect. Hence, we concluded that the desirable requirement of the sub-ppm level field uniformity generation might be barely possible with the current REBCO NMR magnet design approach., (© 2024. The Author(s).)

Objective: As a result of conflicting, inadequate or controversial data in the literature, several issues concerning the management of patients with abdominal aortic aneurysms (AAAs) remain unanswered. The aim of this international, expert-based Delphi consensus document was to provide some guidance for clinicians on these controversial topics., Methods: A three-round Delphi consensus document was produced with 44 experts on 6 prespecified topics regarding the management of AAAs. All answers were provided anonymously. The response rate for each round was 100%., Results: Most participants (42 of 44 [95.4%]) agreed that a minimum case volume per year is essential (or probably essential) for a center to offer open or endovascular AAA repair (EVAR). Furthermore, 33 of 44 (75.0%) believed that AAA screening programs are (probably) still clinically effective and cost effective. Additionally, most panelists (36 of 44 [81.9%]) voted that surveillance after EVAR should be (or should probably be) lifelong. Finally, 35 of 44 participants (79.7%) thought that women smokers should (or should probably/possibly) be considered for screening at 65 years of age, similar to men. No consensus was achieved regarding lowering the threshold for AAA repair and the need for deep venous thrombosis prophylaxis in patients undergoing EVAR., Conclusions: This expert-based Delphi consensus document provides guidance for clinicians regarding specific unresolved issues. Consensus could not be achieved on some topics, highlighting the need for further research in those areas., Competing Interests: Disclosures A.K. has received speaker fees from Cook Inc., & W.L. Gore & Associates, and is a consultant for Bentley Innomed. M.A.F. has received clinical trial support and is a Consultant for Cook, W. L. Gore & Associates, Getinge, and ViTAA. He has received research support from Cook and has stock options in Centerline Biomedical. M.E. is a paid consultant for W. L. Gore & Associates and Silk Road Medical. M.G. is a consultant for Cook Medical, W. L. Gore & Associates and Medtronic and a proctor for Cook Medical., (Copyright © 2024 Society for Vascular Surgery. All rights reserved.)

Objective: Implicit bias is a potential factor in the severity of examinee rating during oral examinations. Ratings may be impacted by examinee characteristics, such as gender, that are independent of examinee knowledge base, clinical judgment, or test-taking ability. The effects of examiner-examinee gender concordance in the Vascular Surgery Certifying Examination (VCE) have not been previously studied. We explored whether examiner ratings and likelihood of passing the examination were influenced by gender concordance among examiners and examinees., Methods: Data collected from examinees who first attempted the VCE between 2018 and 2023 were analyzed. There were 1005 examinees (69.3% male and 30.1% female) and 121 examiners (71.9% male, and 28.1% female). Linear mixed-effects models and generalized linear mixed-effects models were used to evaluate the effects of examinee and examiner gender on VCE ratings and likelihood of passing the examination., Results: Examiner-examinee gender concordance had no significant impact on examiner ratings or likelihood of passing the examination. In addition, examinee gender alone had no significant impact on VCE rating or pass rates. Only Vascular Qualifying Examination scores explained more than 1% of the variance in total VCE scores for the gender model (F(1, 1003.5) = 71.08, P < .01, R 2  = 3%). Vascular Qualifying Examination scores were positively related to total VCE scores., Conclusions: Although implicit bias has the potential to impact examiner scoring, there is no evidence that this is the case with respect to gender in the VCE of the American Board of Surgery., Competing Interests: Disclosures None., (Published by Elsevier Inc.)

Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer's disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1β2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brain's endogenous γ-oscillations through enhancing the function of PV+INs., Competing Interests: Competing interests statement:Composition and methods for treating neurodgenerative diseases. W.I.P. Organization, ed. (The Regents of the University of California).

Background: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging., Methods: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed., Findings: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed p non-inferiority =0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed p non-inferiority =0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05])., Interpretation: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible., Funding: Australian National Health Medical Research Council; Boehringer Ingelheim., Competing Interests: Declaration of interests MWP is on a Boehringer-Ingelheim Advisory Board for metalyse in stroke. FCN has received grants from the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia. AM participates on an advisory board for Boehringer Ingelheim and is a World Stroke Organisation board member. HSM reports grants from the British Heart Foundation, the Medical Research Council, the Alzheimer's Society, and the Stroke Association UK, and is the editor-in-chief of the World Stroke Organisation journal, International Journal of Stroke. HM has received speaking fees from the Indonesian Stroke Society and reports travel support for investigator meetings. TGP has received speaking fees from Bayer, Boehringer Ingelheim, Pfizer, and BMS. JFA reports consulting fees from Amgen, Medtronic, and BMS-Pfizer, reports speaking fees from Medtronic and BMS–Pfizer, reports travel support from Daiichi–Sankyo, participates on the advisory board for the WE-TRUST trial, and reports research grants from the Spanish Ministry of Science, the European Commission, and Astra Zeneca. RSG has received travel support from Boehringer Ingelheim. SA has received funding from the UK Stroke Clinical Research Network. KSB is in a spousal relationship with an employee of Boehringer Ingelheim and has received speaking fees from Boehringer Ingelheim and AstraZeneca. All other authors report no disclosures., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Chronic rhinosinusitis (CRS) is common in people with cystic fibrosis (PwCF). Rhinologic symptom prioritization and areas that influence CRS treatment choices, including pursuing endoscopic sinus surgery (ESS), remain understudied., Methods: Adult PwCF + CRS were enrolled at eight centers into a prospective, observational study (2019-2023). Participants were administered the 22-SinoNasal Outcome Test (SNOT-22) survey and a modified SNOT-22 instrument examining symptom importance. We determined importance rankings for individual symptoms and SNOT-22 symptom importance subdomains in two sets of subgroups-those pursuing ESS versus continuing medical management (CMT), and those on elexacaftor/tezacaftor/ivacaftor (ETI) versus not on ETI., Results: Among 69 participants, the highest priorities were nasal congestion (n = 48, 69.6% important), post-nasal discharge (32, 46.4%), facial pain (29, 43.3%), waking up tired (27, 39.1%), and fatigue (26, 37.7%). Those electing surgery (n = 23) prioritized sleep and psychological dysfunction symptoms compared to those pursuing CMT (n = 49) (sleep median score = 19.0 [interquartile range: 12.0, 25.0] vs. 4.5 [0.0, 12.8]; p < 0.0001; psychological = 17.0 [7.0, 26.0] vs. 7.0 [0.0, 15.8]; p = 0.002). ETI users had comparable SNOT-22 total symptom importance scores to non-ETI users (p = 0.14). Non-ETI users (n = 34) showed a trend toward prioritizing sleep symptoms compared to ETI users (n = 35) (13.0 [2.8, 22.3] vs. 6.0 [2.0, 17.0]; p = 0.055)., Conclusions: Nasal congestion and post-nasal discharge were top priorities reported by PwCF + CRS. Those electing surgery prioritized sleep and psychological symptoms, highlighting their importance in pre-operative discussions. Non-ETI users' prioritization of sleep improvement may highlight their unique disease impact and therapeutic needs; however, additional investigation is required., (© 2024 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Objectives: Emergency department (ED) overcrowding presents a global challenge that inhibits prompt care for critically ill patients. Traditional 5-level triage system that heavily rely on the judgment of the triage staff could fail to detect subtle symptoms in critical patients, thus leading to delayed treatment. Unlike previous rivalry-focused approaches, our study aimed to establish a collaborative machine learning (ML) model that renders risk scores for severe illness, which may assist the triage staff to provide a better patient stratification for timely critical cares., Methods: This retrospective study was conducted at a tertiary teaching hospital. Data were collected from January 2015 to October 2022. Demographic and clinical information were collected at triage. The study focused on severe illness as the outcome. We developed artificial neural network (ANN) models, with or without utilizing the Taiwan Triage and Acuity Scale (TTAS) score as one of the predictors. The model using the TTAS score is termed a machine-human collaborative model (ANN-MH), while the model without it is referred to as a machine-only model (ANN-MO). The predictive power of these models was assessed using the area under the receiver-operating-characteristic (AUROC) and the precision-recall curves (AUPRC); their sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1 score were compared., Results: The study analyzed 668,602 ED visits from 2015 to 2022. Among them, 278,724 visits from 2015 to 2018 were used for model training and validation, while 320,201 visits from 2019 to 2022 were for testing model performance. Approximately 2.6% of visits were by severely ill patients, whose TTAS scores ranged from 1 to 5. The ANN-MH model achieved a testing AUROC of 0.918 and AUPRC of 0.369, while for the ANN-MO model the AUROC and AUPRC were 0.909 and 0.339, respectively. Based on these metrics, the ANN-MH model outperformed the ANN-MO model, and both surpassed human triage classification. Subgroup analyses further highlighted the models' capability to identify higher-risk patients within the same triage level., Conclusions: The traditional 5-level triage system often falls short, leading to under-triage of critical patients. Our models include a score-based differentiation within a triage level to offer advanced risk stratification, thereby promoting patient safety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Accurately predicting the prognosis of ischemic stroke patients after discharge is crucial for physicians to plan for long-term health care. Although previous studies have demonstrated that machine learning (ML) shows reasonably accurate stroke outcome predictions with limited datasets, to identify specific clinical features associated with prognosis changes after stroke that could aid physicians and patients in devising improved recovery care plans have been challenging. This study aimed to overcome these gaps by utilizing a large national stroke registry database to assess various prediction models that estimate how patients' prognosis changes over time with associated clinical factors. To properly evaluate the best predictive approaches currently available and avoid prejudice, this study employed three different prognosis prediction models including a statistical logistic regression model, commonly used clinical-based scores, and a latest high-performance ML-based XGBoost model. The study revealed that the XGBoost model outperformed other two traditional models, achieving an AUROC of 0.929 in predicting the prognosis changes of stroke patients followed for 3 months. In addition, the XGBoost model maintained remarkably high precision even when using only selected 20 most relevant clinical features compared to full clinical datasets used in the study. These selected features closely correlated with significant changes in clinical outcomes for stroke patients and showed to be effective for predicting prognosis changes after discharge, allowing physicians to make optimal decisions regarding their patients' recovery., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Prior studies suggest female sex is associated with worse outcomes after complex endovascular aortic aneurysm repair (EVAR) due to anatomic differences. Therefore, we aimed to compare 30-day perioperative and long-term outcomes after complex EVAR by sex., Methods: A single-center retrospective review of consecutive elective and emergent complex EVAR with company-manufactured devices, laser fenestration, snorkel/periscope, or octopus technique was performed from 2012-2023. The primary outcome was a composite endpoint of any major adverse event (MAE), new-onset dialysis, or death within 30 days. Secondary 30-day technical and long-term outcomes were also assessed., Results: 293 patients (57 females, 19%), mean age 74 years, underwent complex EVAR with commercially available Zenith fenestrated endovascular graft (71%), p-Branch (2%), laser fenestration (8%), snorkel/periscope (16%), or octopus (2%) techniques. Females had significantly different aneurysm-related anatomic characteristics compared to males, including smaller aneurysm diameters (58 ± 7.2 vs. 64 ± 13.2 mm, P < 0.001), more involved aneurysm extent (21.7% vs. 9.8% thoracoabdominal, P = 0.04), increased renal artery calcification (43.9% vs. 27.1%, P = 0.01), and smaller iliac (7.6 ± 1.3 vs. 8.9 ± 1.8 mm, P < 0.01). Operative outcomes were similar; however, females had a greater need for adjunctive access conduits (21.1% vs. 10.6%, P = 0.04), lower technical success (91.2% vs. 98.3%, P = 0.02), and longer median [interquartile range] length of stay (3.0 [4.0] vs. 2.0 [2.5] days, P < 0.001). The composite 30-day outcome of any MAE, new dialysis, or death was not significantly different (15.8% females vs. 11.4% males, P = 0.37). Technical endpoints including 30-day rates of target artery occlusion and type 1 or 3 endoleak were also similar between groups. At mean follow-up of nearly 3 years, females had significantly lower rate of renal function decline (16.0% vs. 41.9%, P < 0.001), but no differences were found in long-term all-cause mortality, aneurysm sac regression, reintervention, or total follow-up imaging studies between groups., Conclusions: Females undergoing complex EVAR had challenging anatomy with higher intraoperative target artery occlusion, conduit use, and longer length of stay. However, 30-day and long-term outcomes were similar, suggesting females can undergo complex EVAR with high technical success and comparable perioperative outcomes to males. Females appeared to have protection from long-term renal function decline, which will be important for future study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Xist, a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However, Xist's ability to diffuse under select circumstances has also been documented, leading us to suspect that Xist RNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as models, we demonstrate that Xist RNA indeed can localize beyond the Xi. However, its binding is limited to ~100 genes in cells undergoing XCI (ES cells) and in post-XCI cells (MEFs). The target genes are diverse in function but are unified by their active chromatin status. Xist binds discretely to promoters of target genes in neighborhoods relatively depleted for Polycomb marks, contrasting with the broad, Polycomb-enriched domains reported for human XIST RNA. We find that Xist binding is associated with down-modulation of autosomal gene expression. However, unlike on the Xi, Xist binding does not lead to full silencing and also does not spread beyond the target gene. Over-expressing Xist in transgenic ES cells similarly lead to autosomal gene suppression, while deleting Xist's Repeat B motif reduces autosomal binding and perturbs autosomal down-regulation. Furthermore, treating female ES cells with the Xist inhibitor, X1, leads to loss of autosomal suppression. Altogether, our findings reveal Xist targets ~100 genes beyond the Xi, identify Repeat B as a crucial domain for its in-trans function in mice, and indicate that autosomal targeting can be disrupted by the X1 small molecule inhibitor.

Currently, coating with anti-reflective materials is an attractive approach to improve the quality of screen-based displays. In this study, mesoporous silica particles were systematically synthesized as a function of surfactant (i.e., CTAC-cetyltrimethylammonium chloride) concentration to serve as main coating fillers possessing low refractive indices. Precisely changing the amount of the CTAC surfactant, silica sol with an average diameter of 50 nm exhibits distinctively different specific surface areas, pore size, and pore volume. Prior to the preparation of final coating solutions containing these silica particle fillers, the percentage of solid content was optimized on a glass slide. The use of 50 wt% solid content exhibited the highest transmittance of light. Among various content levels of silica sol, the use of 3.5 wt% of silica particles in the solid content displayed the highest transmittance (i.e., best anti-reflectiveness). Under the almost identical coating layers prepared with the fixed amount of silica particles possessing different surface areas, pore size, and pore volume, it appears that the largest pore volume played the most important role in improving the anti-reflective properties. Experimentally understanding the key feature of low-refractive filler materials under the optimized conditions could provide a clear view to develop highly effective anti-reflective materials for various display applications.

Background: Sociodemographic status (SDS) including race/ethnicity and socioeconomic status as approximated by education, income, and insurance status impact pulmonary disease in people with cystic fibrosis (PwCF). The relationship between SDS and chronic rhinosinusitis (CRS) remains understudied., Methods: In a prospective, multi-institutional study, adult PwCF completed the 22-Question SinoNasal Outcome Test (SNOT-22), Smell Identification Test (SIT), Questionnaire of Olfactory Disorder Negative Statements (QOD-NS), and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Lund-Kennedy scores, sinus computed tomography, and clinical data were collected. Data were analyzed across race/ethnicity, sex, and socioeconomic factors using multivariate regression., Results: Seventy-three PwCF participated with a mean age of 34.7 ± 10.9 years and 49 (67.1%) were female. Linear regression identified that elexacaftor/tezacaftor/ivacaftor (ETI) use (β = ‒4.09, 95% confidence interval [CI] [‒6.08, ‒2.11], p < 0.001), female sex (β = ‒2.14, 95% CI [‒4.11, ‒0.17], p = 0.034), and increasing age (β = ‒0.14, 95% CI [‒0.22, ‒0.05], p = 0.003) were associated with lower/better endoscopy scores. Private health insurance (β = 17.76, 95% CI [5.20, 30.32], p = 0.006) and >16 educational years (β = 13.50, 95% CI [2.21, 24.80], p = 0.020) were associated with higher baseline percent predicted forced expiratory volume in one second (ppFEV 1 ). Medicaid/Medicare insurance was associated with worse endoscopy scores, CFQ-R respiratory scores, and ppFEV 1 (all p < 0.017), and Hispanic/Latino ethnicity was associated with worse SNOT-22 scores (p = 0.047), prior to adjustment for other cofactors. No other SDS factors were associated with SNOT-22, QOD-NS, or SIT scores., Conclusions: Differences in objective measures of CRS severity exist among PwCF related to sex, age, and ETI use. Variant status and race did not influence patient-reported CRS severity measures or olfaction in this study. Understanding how these factors impact response to treatment may improve care disparities among PwCF., Clinical Trials: NCT04469439., (© 2024 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common cause of chronic hepatitis in adult and pediatric patients. Adolescents with severe MASLD can demonstrate a more aggressive disease phenotype as they more commonly develop liver fibrosis than BMI matched adults. Therefore, MASLD is the fastest growing indication for liver transplants in young adults., Methods: Pioglitazone has been shown to improve liver histology in adult patients with MASLD, and in some studies, it attenuated liver fibrosis. Despite its perceived efficacy, pioglitazone is not widely used, likely due to its side effect profile, specifically increased weight gain. Topiramate lowers body weight in adolescents and in combination with phentermine, is one of the few FDA-approved medications for the management of obesity in children over 12 years of age. We performed a retrospective review of the outcomes in pediatric patients with severe MASLD, treated with the combined pioglitazone and topiramate therapy., Results: Here, we report a case series of seven adolescents with severe MASLD and ≥F2 liver fibrosis treated with the combined pioglitazone and topiramate therapy. The combined therapy improved mean serum ALT from 165 ± 80 U/L to 89 ± 62 U/L after 12 months mean duration of treatment. One patient who completed 24 months of the combined therapy demonstrated a decrease in liver stiffness from 8.9 kPa to 5.6 kPa, as assessed by FibroScan elastography. There was a significant increase in body weight during this time, however, body mass index as a percentage of the 95 th percentile adjusted for age and gender did not increase significantly, 151 ± 29% vs. 152 ± 28%. Moreover, waist circumference, mid-upper arm circumference, percent body fat, and muscle mass were not significantly different before and after treatment. Serum lipid levels and hemoglobin A1c also did not change with the treatment., Conclusion: In summary, this case series provides encouraging results about the efficacy of the combined pioglitazone and topiramate therapy for the management of adolescents with severe MASLD, which should be further explored in clinical studies., (Copyright © 2024 Copyright: © 2024 Saudi Journal of Gastroenterology.)

Objective: This paper explores the role of depressive symptoms (mediator/moderator) in the association between physical multimorbidity (exposure) and cognitive function (outcome) among older adults in the three most populous middle-income countries., Methods: This study used cross-sectional data from China (2015 China Health and Retirement Longitudinal Study), India (2017/2018 Longitudinal Ageing Study in India), and Indonesia (2014/2015 Indonesian Family Life Survey), with a total sample of 73,199 respondents aged ≥ 45 years. Three domains of cognitive tests were harmonised across surveys, including time orientation, word recall, and numeracy. The four-way decomposition analysis assessed the mediation and interaction effects between exposure, mediator/moderator, and outcome, adjusted for covariates., Results: The mean age of the respondents (in years) was slightly younger in Indonesia (56.0, SD = 8.8) than in China (59.5, SD = 9.3) and India (60.0, SD = 10.5). The proportion of male respondents was 49.3 % in China, 47.3 % in India, and 47.5 % in Indonesia. Respondents in China had the highest mean cognitive function z scores (54.7, SD = 19.9), followed by India (51.1, SD = 20.0) and Indonesia (51.0, SD = 18.4). Physical multimorbidity was associated with lower cognitive function in China and India (p < 0.0001), with 48.4 % and 40.0 % of the association explained by the mediating effect of depressive symptoms ('overall proportion due to mediation'). The association was not found in Indonesia., Conclusion: Cognitive functions were lower among individuals with physical multimorbidity, and depressive symptoms mainly explained the association. Addressing depressive symptoms among persons with physical multimorbidity is likely to have not only an impact on their mental health but could prevent cognitive decline., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Primary Sjögren's syndrome (pSS) is an inflammatory autoimmune condition affecting the exocrine glands, which can adversely affect the sexual activities of women with pSS., Objectives: The study sought to evaluate the performance of the Female Sexual Function Index (FSFI) score in women with pSS regarding desire, arousal, orgasm, lubrication, satisfaction, and pain compared with those of healthy individuals., Methods: A systematic review was conducted by examining studies published up to May 2023 using Embase, Web of Science, Scopus, and PubMed with the search terms "sexual" and "Sjögren's syndrome.", Results: Out of the 228 articles retrieved, 9 met the criteria for inclusion in this systematic review. Six of these studies were cross-sectional, involving 229 women with pSS and 303 control subjects. Results from the meta-analysis showed that women with pSS had significantly lower scores in all 6 FSFI subdomains and the total FSFI score compared with healthy individuals. Lubrication showed the largest decrease, followed by pain. In addition, women with pSS exhibited significantly higher standardized mean differences in depression and in anxiety, as assessed by the Hospital Anxiety and Depression Scale, when compared with control subjects., Conclusion: This updated meta-analysis underscores the importance of assessing genitourinary atrophy, disease-related psychological changes, and dyspareunia in women with pSS. It also emphasizes the need for customized therapeutic approaches to address these sexual dysfunctions effectively., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims and Objectives: To investigate the psychological distress, sexual satisfaction, and quality of life of gynaecological cancer survivors and their spouses during cancer survivorship., Background: The survival rate of patients with cancer is increasing owing to advances in medical treatment technology. Spouses are the closest companions of gynaecological cancer survivors. Patients with gynaecological cancer and their spouses face different situations and challenges after experiencing cancer invasion., Design: Questionnaire-based cross-sectional study., Methods: Convenience sampling was employed, and 180 participants, including patients with gynaecological cancer and their spouses, were enrolled. A structured questionnaire was used to investigate the psychological distress, sexual satisfaction, and quality of life of gynaecological cancer survivors and their spouses during acute, extended, and permanent survivorship. The STROBE checklist guided the study preparation., Results: For gynaecological cancer survivors and their spouses, (1) severe psychological distress was present during acute survivorship, with anxiety extending until permanent survivorship; (2) no significant differences were observed in pre- and post-treatment sexual satisfaction, although pre-treatment sexual satisfaction was higher than post-treatment sexual satisfaction in all three cancer survivorship stages and (3) quality of life decreased during acute survivorship and gradually improved with time., Conclusions: Psychological distress, sexual satisfaction and quality of life of gynaecological cancer survivors and their spouses worsened during acute survivorship and improved over time until permanent survivorship., Relevance to Clinical Practice: Gynaecological cancer survivors and their spouses experience anxiety and depression from diagnosis confirmation until permanent survivorship (>5 years survival). Therefore, clinical nurses' sensitivity to emotional distress in cancer survivors and their spouses can be improved and a consistent and routine evaluation method has been established for the early detection of such emotional distress. The results of this study can provide a reference for clinical healthcare professionals and contribute to a better quality of care., (© 2024 John Wiley & Sons Ltd.)

Background: AMD3100, a CXCR4 antagonist, is currently prescribed for activating the mobilization of hematopoietic stem cells. Recently, AMD3100 was shown to potentiate bone morphogenetic protein-2 (BMP-2)-induced bone formation by stimulating the trafficking of mesenchymal cells. However, optimization of the strategic combination of AMD3100 and BMP-2 has not yet been clearly established. The purpose of this study was to evaluate the effect of AMD3100 on BMP-2-induced bone regeneration in vitro and in a mouse calvarial defect healing model., Methods: In vitro osteoblastic differentiation and cell migration after sequential treatments with AMD3100 and BMP-2 were analyzed by alkaline phosphatase (ALP) activity, ALP staining, and calcium accumulation. Migration capacity was evaluated after treating mesenchymal cells with AMD3100 and/or BMP-2. A critical-size calvarial defect model was used to evaluate bone formation after sequential or continuous treatment with AMD3100 and BMP-2. The degree of bone formation in the defect was analyzed using micro-computed tomography (micro-CT) and histological staining., Results: Compared with single treatment using either AMD3100 or BMP-2 alone, sequential treatment with AMD3100 followed by BMP-2 on mesenchymal cells increased osteogenic differentiation. Application of AMD3100 and subsequent BMP-2 significantly activated cell migration on mesenchymal cell than BMP-2 alone or AMD3100 alone. Micro-CT and histomorphometric analysis showed that continuous intraperitoneal (IP) injection of AMD3100 resulted significantly increased new bone formation in BMP-2 loaded scaffold in calvarial defect than control groups without AMD3100 IP injection. Additionally, both single IP injection of AMD3100 and subsequent BMP-2 injection to the scaffold in calvarial defect showed pronounced new bone formation compared to continuous BMP-2 treatment without AMD3100 treatment., Conclusion: Our data suggest that single or continuous injection of AMD3100 can potentiate BMP-2-induced osteoblastic differentiation and bone regeneration. This strategic combination of AMD3100 and BMP-2 may be a promising therapy for bone regeneration., (© 2024. The Author(s).)

Objectives: This is the first systematic review and meta-analysis of the prevalence of multimorbidity, its risk factors including socioeconomic factors, and the consequences of multimorbidity on health systems and broader society in India., Methods: A systematic review of both published and grey literature from five databases (Medline, Embase, EBSCO, Scopus, and ProQuest) was conducted including original studies documenting prevalence or patient outcomes associated with multimorbidity among adults in India. We excluded studies that did not explicitly mention multimorbidity. Three independent reviewers did primary screening based on titles and abstracts followed by full-text review for potential eligibility. The risk of bias was independently assessed by two reviewers following the Appraisal Tool for Cross-Sectional Studies. We presented both qualitative and quantitative (through meta-analysis) summaries of the evidence. The protocol for this study was prospectively registered with PROSPERO (CRD42021257281)., Results: The review identified 5442 articles out of which 35 articles were finally included in this study. Twenty-three studies were based on the primary data while 12 used secondary data. Eleven studies were conducted in hospital/primary care setting while 24 were community-based. The pooled prevalence of multimorbidity based on (n=19) studies included for meta-analysis was 20% (95% CI: 19% to 20%). The most frequent outcomes were increased healthcare utilization, reduced health-related quality of life, physical and mental functioning., Conclusion: We identified a wide variance in the magnitude of multimorbidity across age groups and regions with most of the studies from eastern India. Nation-wide studies, studies on vulnerable populations and interventions are warranted., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Epithelial membrane protein-2 (EMP2) is upregulated in a number of tumors and therefore remains a promising target for mAb-based therapy. In the current study, image-guided therapy for an anti-EMP2 mAb was evaluated by PET in both syngeneic and immunodeficient cancer models expressing different levels of EMP2 to enable a better understanding of its tumor uptake and off target accumulation and clearance. The therapeutic efficacy of the anti-EMP2 mAb was initially evaluated in high- and low-expressing tumors, and the mAb reduced tumor load for the high EMP2-expressing 4T1 and HEC-1-A tumors. To create an imaging agent, the anti-EMP2 mAb was conjugated to p-SCN-Bn-deferoxamine (DFO) and radiolabeled with 89Zr. Tumor targeting and tissue biodistribution were evaluated in syngeneic tumor models (4T1, CT26, and Panc02) and human tumor xenograft models (Ramos, HEC-1-A, and U87MG/EMP2). PET imaging revealed radioactive accumulation in EMP2-positive tumors within 24 hours after injection, and the signal was retained for 5 days. High specific uptake was observed in tumors with high EMP2 expression (4T1, CT26, HEC-1-A, and U87MG/EMP2), with less accumulation in tumors with low EMP2 expression (Panc02 and Ramos). Biodistribution at 5 days after injection revealed that the tumor uptake ranged from 2 to approximately 16%ID/cc. The results show that anti-EMP2 mAbs exhibit EMP2-dependent tumor uptake with low off-target accumulation in preclinical cancer models. The development of improved anti-EMP2 Ab fragments may be useful to track EMP2-positive tumors for subsequent therapeutic interventions., (©2024 American Association for Cancer Research.)

Introduction: Olfactory dysfunction (OD) is common among people with cystic fibrosis (PwCF). The Questionnaire of Olfactory Disorders (QOD) is a validated instrument that evaluates olfactory-specific quality-of-life. The QOD minimal clinically important difference (MCID) and factors associated with olfactory improvement after elexacaftor/tezacaftor/ivacaftor have not been determined for PwCF., Methods: Prospective observational data were pooled from three studies that enrolled adult PwCF with chronic rhinosinusitis (CRS). QOD scores and disease characteristics were assessed. To evaluate internal consistency and calculate the QOD MCID, Cronbach's alpha and four distribution-based methods were employed. For participants who enrolled prior to elexacaftor/tezacaftor/ivacaftor, QOD scores were obtained at baseline and after elexacaftor/tezacaftor/ivacaftor initiation. Multivariable regression was used to identify factors associated with QOD improvement., Results: Of 129 PwCF included, 65 had QOD scores before and 3-6 months after starting elexacaftor/tezacaftor/ivacaftor. Mean baseline QOD score was 6.5 ± 7.9. Mean Cronbach's alpha was ≥0.85. The MCID estimates were as follows: Cohen's effect size = 1.6, standard error of measurement = 2.5, ½ baseline standard deviation = 4.0, and minimal detectable change = 6.9. Mean MCID was 3.7. Of those with pre/post elexacaftor/tezacaftor/ivacaftor QOD scores, the mean change in QOD was -1.3 ± 5.4. After elexacaftor/tezacaftor/ivacaftor, QOD improvement surpassed the MCID in 22% of participants (14/65). Worse baseline QOD scores and nasal polyps were associated with improved QOD scores after elexacaftor/tezacaftor/ivacaftor (both p < 0.04)., Conclusion: The QOD MCID in PwCF was estimated to be 3.7. Elexacaftor/tezacaftor/ivacaftor led to qualitative but not clinically meaningful improvements in QOD score for most PwCF; PwCF with worse baseline QOD scores and nasal polyps improved in a clinically significant manner., (© 2023 ARS‐AAOA, LLC.)

Objective: Fenestrated endovascular aneurysm repair (FEVAR) has become a mainstay in treating complex aortic aneurysms, though baseline patient factors predicting long-term outcomes remain poorly understood. Proteinuria is an early marker for chronic kidney disease and associated with adverse cardiovascular outcomes, but its utility in patients with aortic aneurysms is unknown. We aimed to determine whether preoperative proteinuria impacts long-term survival after FEVAR., Methods: A single-institution, retrospective review of all elective FEVAR was performed. Preoperative proteinuria was assessed by urinalysis: negative (0-29 mg/dL), 1+ (30-100 mg/dL), 2+ (101-299 mg/dL), and 3+ (≥300 mg/dL). The cohort was stratified by patients with proteinuria (≥30 mg/dL) vs those without (<30 mg/dL). Baseline, perioperative, and long-term outcomes were compared. The primary outcome, all-cause mortality, was evaluated by Kaplan-Meier analysis and independent predictors with Cox proportional hazards modeling., Results: Among 181 patients who underwent standard FEVAR from 2012 to 2022 (mean follow-up 33 months), any proteinuria was noted in 30 patients (16.6%). Patients with proteinuria were more likely to be Black (10.0% vs 1.3%) with a lower estimated glomerular filtration rate (eGFR) (52.7 ± 24.7 vs 67.7 ± 20.5 mL/min/1.73 m 2 ), higher Society for Vascular Surgery comorbidity score (10.9 ± 4.3 vs 8.2 ± 4.7) and calcium channel blocker therapy (50.0% vs 29.1%), and larger maximal aneurysm diameter (67.2 ± 16.9 vs 59.8 ± 9.8 mm) (all P < .05). Thirty-day mortality was higher in the proteinuria group (10.0% vs 1.3%; P = .03). Overall survival at 1 and 5 years was significantly lower for those with proteinuria (71.5% vs 92.3% and 29.5% vs 68.1%; log-rank P < .001). On multivariable analysis, preoperative proteinuria was independently associated with over threefold higher hazard of mortality (hazard ratio [HR]: 3.21, 95% confidence interval [CI]: 1.66-6.20; P < .001), whereas preoperative eGFR was not predictive (HR: 0.99, 95% CI: 0.98-1.01; P = .28). Additional significant predictors included chronic obstructive pulmonary disease (HR: 2.04), older age (HR: 1.05), and larger maximal aneurysm diameter (HR: 1.03; all P < .05)., Conclusions: In our 10-year experience with FEVAR, preoperative proteinuria was observed in 17% of patients and was significantly associated with worse survival. In this cohort, proteinuria was independently associated with all-cause mortality, whereas eGFR was not, suggesting that urinalysis may provide an additional simple metric for risk-stratifying patients before FEVAR., Competing Interests: Disclosures None., (Copyright © 2024 Society for Vascular Surgery. All rights reserved.)

How Polycomb repressive complex 2 (PRC2) is regulated by RNA remains an unsolved problem. Although PRC2 binds G-tracts with the potential to form RNA G-quadruplexes (rG4s), whether rG4s fold extensively in vivo and whether PRC2 binds folded or unfolded rG4 are unknown. Using the X-inactivation model in mouse embryonic stem cells, here we identify multiple folded rG4s in Xist RNA and demonstrate that PRC2 preferentially binds folded rG4s. High-affinity rG4 binding inhibits PRC2's histone methyltransferase activity, and stabilizing rG4 in vivo antagonizes H3 at lysine 27 (H3K27me3) enrichment on the inactive X chromosome. Surprisingly, mutagenizing the rG4 does not affect PRC2 recruitment but promotes its release and catalytic activation on chromatin. H3K27me3 marks are misplaced, however, and gene silencing is compromised. Xist-PRC2 complexes become entrapped in the S1 chromosome compartment, precluding the required translocation into the S2 compartment. Thus, Xist rG4 folding controls PRC2 activity, H3K27me3 enrichment, and the stepwise regulation of chromosome-wide gene silencing., Competing Interests: Declaration of interests J.T.L. is a cofounder of Fulcrum Therapeutics, a scientific adviser to Skyhawk Therapeutics, and a Non-Executive Director of GSK., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Hyperglycemia affects the outcomes of endovascular therapy (EVT) for acute ischemic stroke (AIS). This study compares the predictive ability of diabetes status and glucose measures on EVT outcomes using nationwide registry data., Methods: The study included 1,097 AIS patients who underwent EVT from the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke. The variables analyzed included diabetes status, admission glucose, glycated hemoglobin (HbA1c), admission glucose-to-HbA1c ratio (GAR), and outcomes such as 90-day poor functional outcome (modified Rankin Scale score ≥ 2) and symptomatic intracranial hemorrhage (SICH). Multivariable analyses investigated the independent effects of diabetes status and glucose measures on outcomes. A receiver operating characteristic (ROC) analysis was performed to compare their predictive abilities., Results: The multivariable analysis showed that individuals with known diabetes had a higher likelihood of poor functional outcomes (odds ratios [ORs] 2.10 to 2.58) and SICH (ORs 3.28 to 4.30) compared to those without diabetes. Higher quartiles of admission glucose and GAR were associated with poor functional outcomes and SICH. Higher quartiles of HbA1c were significantly associated with poor functional outcomes. However, patients in the second HbA1c quartile (5.6-5.8%) showed a non-significant tendency toward good functional outcomes compared to those in the lowest quartile (<5.6%). The ROC analysis indicated that diabetes status and admission glucose had higher predictive abilities for poor functional outcomes, while admission glucose and GAR were better predictors for SICH., Conclusion: In AIS patients undergoing EVT, diabetes status, admission glucose, and GAR were associated with 90-day poor functional outcomes and SICH. Admission glucose was likely the most suitable glucose measure for predicting outcomes after EVT., Competing Interests: 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hsieh, Hsieh, Yang, Sung, Hsieh, Lee, Lin, Chen, Lin, Sung, Tang, Chu, Tsai, Chou, Lin, Wei, Chen, Yan, Chen, Hsiao, Chan, Huang, Liu, Tang, Lee, Lien, Chiou, Lee and Jeng.)

Background: Long-term exposure to PM 2.5 has been linked to increased mortality risk. However, limited studies have examined the potential modifying effect of community-level characteristics on this association, particularly in Asian contexts. This study aimed to estimate the effects of long-term exposure to PM 2.5 on mortality in South Korea and to examine whether community-level deprivation, medical infrastructure, and greenness modify these associations., Methods: We conducted a nationwide cohort study using the National Health Insurance Service-National Sample Cohort. A total of 394,701 participants aged 30 years or older in 2006 were followed until 2019. Based on modelled PM 2.5 concentrations, 1 to 3-year and 5-year moving averages of PM 2.5 concentrations were assigned to each participant at the district level. Time-varying Cox proportional-hazards models were used to estimate the association between PM 2.5 and non-accidental, circulatory, and respiratory mortality. We further conducted stratified analysis by community-level deprivation index, medical index, and normalized difference vegetation index to represent greenness., Results: PM 2.5 exposure, based on 5-year moving averages, was positively associated with non-accidental (Hazard ratio, HR: 1.10, 95% Confidence Interval, CI: 1.01, 1.20, per 10 µg/m 3 increase) and circulatory mortality (HR: 1.22, 95% CI: 1.01, 1.47). The 1-year moving average of PM 2.5 was associated with respiratory mortality (HR: 1.33, 95% CI: 1.05, 1.67). We observed higher associations between PM 2.5 and mortality in communities with higher deprivation and limited medical infrastructure. Communities with higher greenness showed lower risk for circulatory mortality but higher risk for respiratory mortality in association with PM 2.5 ., Conclusions: Our study found mortality effects of long-term PM 2.5 exposure and underlined the role of community-level factors in modifying these association. These findings highlight the importance of considering socio-environmental contexts in the design of air quality policies to reduce health disparities and enhance overall public health outcomes., (© 2024. The Author(s).)

A base-mediated, three-component synthesis of symmetric and unsymmetric pyran-fused biscoumarins via the coupling of 4-hydroxycoumarin with 4-chloro-3-formylcoumarin in ethanol is reported. This methodology is further extended to the construction of various indole/coumarin-substituted symmetric pyran-fused biscoumarins. The unsymmetric pyran-fused biscoumarin can react with amines and 4-hydroxycoumarins under basic and acidic conditions to afford pyridinone-fused coumarins and pyranone-fused coumarins, respectively. The mechanisms of their formation are proposed., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Lyme disease (LD), caused by spirochete bacteria of the genus Borrelia burgdorferi sensu lato , remains the most common vector-borne disease in the northern hemisphere. Borrelia outer surface protein A (OspA) is an integral surface protein expressed during the tick cycle, and a validated vaccine target. There are at least 20 recognized Borrelia genospecies, that vary in OspA serotype. This study presents a new in silico sequence-based method for OspA typing using next-generation sequence data. Using a compiled database of over 400 Borrelia genomes encompassing the 4 most common disease-causing genospecies, we characterized OspA diversity in a manner that can accommodate existing and new OspA types and then defined boundaries for classification and assignment of OspA types based on the sequence similarity. To accommodate potential novel OspA types, we have developed a new nomenclature: OspA in silico type (IST). Beyond the ISTs that corresponded to existing OspA serotypes 1-8, we identified nine additional ISTs that cover new OspA variants in B. bavariensis (IST9-10), B. garinii (IST11-12), and other Borrelia genospecies (IST13-17). The IST typing scheme and associated OspA variants are available as part of the PubMLST Borrelia spp. database. Compared to traditional OspA serotyping methods, this new computational pipeline provides a more comprehensive and broadly applicable approach for characterization of OspA type and Borrelia genospecies to support vaccine development.

Introduction: Free flap transfer for head and neck defects has gained worldwide acceptance. Because flap failure is a devastating outcome, studies have attempted to identify risk factors-including renal failure. We sought to determine whether end-stage renal disease (ESRD) patients undergoing dialysis are at increased risk of flap failure following microsurgical head and neck reconstruction., Patients and Methods: The study's participants were patients who underwent free flap reconstruction in the head and neck region at Hualien Tzu Chi Hospital between January 2010 and December 2019. We used the National Health Insurance "Specific Diagnosis and Treatment Code" to identify patients undergoing dialysis; these patients comprised the dialysis group, whose members were matched to a non-dialysis group for age and gender. The dependent variables were flap survival rate, take-back rate, and flap failure risk between the dialysis and non-dialysis groups., Results: We included 154 patients in the dialysis (n = 14) and non-dialysis (n = 140) groups. The groups were similar in terms of age and most comorbidities, except diabetes mellitus, hypertension, and coronary artery disease, which were more prevalent in the dialysis group. The dialysis and non-dialysis groups had similar flap survival rates (100% vs. 92.9%; p = .600). Twenty-three patients underwent take-back surgery, most in the non-dialysis group (14.3% vs. 15.0%; p = 1.000). Patients in the dialysis group were more likely to have prolonged intensive care unit stays; however, dialysis alone did not predict flap failure (OR: 0.83; p = .864)., Conclusion: This study found no significant differences in free flap survival and take-back rates between patients with and without dialysis. Dialysis did not increase the risk of flap failure following microsurgical head and neck reconstruction in this study; however, prospective, randomized controlled trials are needed., (© 2024 Wiley Periodicals LLC.)

Introduction: In patients with idiopathic normal pressure hydrocephalus (iNPH), the characteristics of balance disturbance are not as well understood as those related to gait. This study examined changes in postural stability in quiet standing after the cerebrospinal fluid tap test (CSFTT) in these patients. Furthermore, the study explored the relationship between the amount of spontaneous body sway and both gait and executive function., Materials and Methods: All patients diagnosed with iNPH underwent CSFTT. We evaluated their center of pressure (COP) measurements on a force plate during quiet standing, both pre- and post-CSFTT. Following the COP measurements, we calculated COP parameters using time and frequency domain analysis and assessed changes in these parameters after CSFTT. At pre-CSFTT, we assessed the Timed Up and Go (TUG) and the Frontal Assessment Battery (FAB). We investigated the relationship between COP parameters and the TUG and FAB scores at pre-CSFTT., Results: A total of 72 patients with iNPH were initially enrolled, and 56 patients who responded positively to CSFTT were finally included. Post-CSFTT, significant improvements were observed in COP parameters through time domain analysis. These included the velocity of COP (vCOP), root-mean-square of COP (rmsCOP), turn index, torque, and base of support (BOS), compared to the pre-CSFTT values ( p  < 0.05). In the frequency domain analysis of COP parameters post-CSFTT, there was a decrease in both the peak and average of power spectral density (PSD) values in both the anteroposterior (AP) and mediolateral (ML) directions below 0.5 Hz ( p  < 0.05). In addition, the TUG scores showed a positive correlation with vCOP, rmsCOP, turn index, torque, BOS, and both the peak and average PSD values in the AP and ML directions below 0.5 Hz ( p  < 0.05). The FAB scores demonstrated a negative correlation with vCOP, rmsCOP, turns index, BOS, and both peak and average PSD values in the AP direction below 0.5 Hz ( p  < 0.05)., Conclusion: In patients with iNPH who responded to CSFTT, there was an improvement in spontaneous body sway during quiet standing after CSFTT. Increased spontaneous sway is associated with impaired gait and frontal lobe function. This may be linked to impaired cortico-cortical and cortico-subcortical circuits in patients with iNPH., Competing Interests: 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., (Copyright © 2024 Park, Lee, Jung, Park, Lee and Kang.)