Residential greenness and lower breast and prostate cancer incidence: Evidence from a retrospective cohort study of 977,644 participants from Israel.

BACKGROUND: There is limited evidence on the associations between residential greenness and cancer incidence in longitudinal studies. OBJECTIVES: The aim of the study was to evaluate the associations between weighted mean residential greenness exposure and cancer incidence. METHODS: This is a registry based retrospective cohort study of 977,644 participants. The residential greenness exposure was estimated for every participant, as the weighted mean residential greenness exposure. This was based on the mean Normalized Difference Vegetation Index (NDVI) in the residential small geographic area and the duration of the residence in this area. Cancer incidence cases included consecutive newly diagnosed cases of primary cancer. Analyses were conducted for all cancer sites, lung cancer, bladder cancer, breast cancer, prostate cancer and melanoma-skin cancer. Cox regression models were used to evaluate the crude and adjusted associations (hazards ratios (HR) and its 95 % confidence intervals (CIs)) between tertiles of residential greenness and cancer incidence. Further adjusted models to nitrogen oxides (NOx) were estimated. RESULTS: After adjustment to covariates, exposure to the highest tertile of residential greenness, compared to the lowest, were associated with lower risk for all cancer sites (HR = 0.88, 95 % CI: 0.86-0.90), breast cancer (HR = 0.85, 95 % CI: 0.80-0.89) and prostate cancer (HR = 0.85, 95 % CI: 0.79-0.91). In addition, lower risk were observed for the middle tertile of exposure and all cancer sites (HR = 0.88, 95 % CI: 0.86-0.90), breast cancer (HR = 0.88, 95 % CI: 0.84-0.92) and prostate cancer (HR = 0.83, 95 % CI: 0.79-0.89). There was no evidence for mediation by air pollution (NOx). DISCUSSION: Residential greenness demonstrated beneficial associations with lower risk for all cancers, breast and prostate cancers. If our observations will be replicated, it may present a useful avenue for public-health intervention to reduce cancer burden through the provision of greenness exposure.

[Bolus obstruction within the esophagus - an analysis over 5 years]. / Bolusobstruktionen im Ösophagus ­ Eine Analyse über 5 Jahre.

BACKGROUND: The removal of bolus impaction within the esophagus is an indication for emergency endoscopy. The current guideline of the European Society of Gastrointestinal Endoscopy (ESGE) recommends gently pushing the bolus into the stomach. This view is discerned by many endoscopists because of the increased risk of complications. In addition, the use of an endoscopic cap for bolus removal is not mentioned. MATERIAL AND METHODS: In a retrospective analysis from 2017 to 2021 we investigated 66 adults and 11 children with acute bolus impaction within the esophagus. RESULTS: Eosinophilic esophagitis, reflux esophagitic /peptic stenosis and Schatzki Ring caused 57.6%, esophageal and bronchial carcinoma 18%, esophageal motility disorders 4.5%, Zenkers diverticulum 1.5% and radiation esophagitis 1.5% of the bolus obstructions. The reason remained unclear in 16.7% of the cases. The spectrum was comparable in children with additional 2 cases with esophageal atresia and stenosis. The reason was unclear in 2 cases. Removal of bolus impaction was successful in 92.4% in adults and 100% in children. Bolus obstruction in adults was successfully removed solely by endoscopic cap in 57.6% and 75% in children. Pushing the bolus into the stomach without disintegration was possible in only 9% of cases. CONCLUSION: Flexible endoscopy is an effective ermergency intervention for removal of bolus obstruction within the esophagus. Uncontrolled pushing the bolus into the stomach without view cannot be recommended. An endoscopic cap is a good extension for safe bolus removal.

"It's Better If I Die Because Even in the Hospital, There is a Stigma, People Still Gossip": Gossip as a Culturally Shaped Labeling Process and Its Implications for HIV-Related Stigma in Botswana.

This study qualitatively explores HIV-related gossip as both a manifestation and driver of HIV-related stigma, which is a known barrier to HIV testing and treatment in Botswana. Data were elicited from 5 focus group discussions and 46 semi-structured in-depth interviews with individuals living with HIV and community members with undisclosed serostatus in Gaborone, Botswana in 2017 (n = 84). Directed content analysis using the 'What Matters Most' theoretical framework identified culturally salient manifestations of HIV-related stigma; simultaneous use of Modified Labeling Theory allowed interpretation and stepwise organization of how the social phenomenon of gossip leads to adverse HIV outcomes. Results indicated that HIV-related gossip can diminish community standing through culturally influenced mechanisms, in turn precipitating poor psychosocial well-being and worsened HIV-related outcomes. These harms may be offset by protective factors, such as appearing healthy, accepting one's HIV status, and community education about the harms of gossip.

Loss of Independent Living in Patients Undergoing Transcatheter or Surgical Aortic Valve Replacement: A Retrospective Cohort Study.

BACKGROUND: The recommendation for transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) in patients 65 to 80 years of age is equivocal, leaving patients with a difficult decision. We evaluated whether TAVR compared to SAVR is associated with reduced odds for loss of independent living in patients ≤65, 66 to 79, and ≥80 years of age. Further, we explored mechanisms of the association of TAVR and adverse discharge. METHODS: Adult patients undergoing TAVR or SAVR within a large academic medical system who lived independently before the procedure were included. A multivariable logistic regression model, adjusting for a priori defined confounders including patient demographics, preoperative comorbidities, and a risk score for adverse discharge after cardiac surgery, was used to assess the primary association. We tested the interaction of patient age with the association between aortic valve replacement (AVR) procedure and loss of independent living. We further assessed whether the primary association was mediated (ie, percentage of the association that can be attributed to the mediator) by the procedural duration as prespecified mediator. RESULTS: A total of 1751 patients (age median [quartiles; min-max], 76 [67, 84; 23-100]; sex, 56% female) were included. A total of 27% (222/812) of these patients undergoing SAVR and 20% (188/939) undergoing TAVR lost the ability to live independently. In our cohort, TAVR was associated with reduced odds for loss of independent living compared to SAVR (adjusted odds ratio [OR adj ] 0.19 [95% confidence interval {CI}, 0.14-0.26]; P < .001). This association was attenuated in patients ≤65 years of age (OR adj 0.63 [0.26-1.56]; P = .32) and between 66 and 79 years of age (OR adj 0.23 [0.15-0.35]; P < .001), and magnified in patients ≥80 years of age (OR adj 0.16 [0.10-0.25]; P < .001; P -for-interaction = .004). Among those >65 years of age, a shorter procedural duration mediated 50% (95% CI, 28-76; P < .001) of the beneficial association of TAVR and independent living. CONCLUSIONS: Patients >65 years of age undergoing TAVR compared to SAVR had reduced odds for loss of independent living. This association was partly mediated by shorter procedural duration. No association between AVR approach and the primary end point was found in patients ≤65 years of age.

The association of intraoperative low driving pressure ventilation and nonhome discharge: a historical cohort study.

PURPOSE: To evaluate whether intraoperative ventilation using lower driving pressure decreases the risk of nonhome discharge. METHODS: We conducted a historical cohort study of patients aged ≥ 60 yr who were living at home before undergoing elective, noncardiothoracic surgery at two tertiary healthcare networks in Massachusetts between 2007 and 2018. We assessed the association of the median driving pressure during intraoperative mechanical ventilation with nonhome discharge using multivariable logistic regression analysis, adjusted for patient and procedural factors. Contingent on the primary association, we assessed effect modification by patients' baseline risk and mediation by postoperative respiratory failure. RESULTS: Of 87,407 included patients, 12,584 (14.4%) experienced nonhome discharge. In adjusted analyses, a lower driving pressure was associated with a lower risk of nonhome discharge (adjusted odds ratio [aOR], 0.88; 95% confidence interval [CI], 0.83 to 0.93, per 10 cm H2O decrease; P < 0.001). This association was magnified in patients with a high baseline risk (aOR, 0.77; 95% CI, 0.73 to 0.81, per 10 cm H2O decrease, P-for-interaction < 0.001). The findings were confirmed in 19,518 patients matched for their baseline respiratory system compliance (aOR, 0.90; 95% CI, 0.81 to 1.00; P = 0.04 for low [< 15 cm H2O] vs high [≥ 15 cm H2O] driving pressures). A lower risk of respiratory failure mediated the association of a low driving pressure with nonhome discharge (20.8%; 95% CI, 15.0 to 56.8; P < 0.001). CONCLUSIONS: Intraoperative ventilation maintaining lower driving pressure was associated with a lower risk of nonhome discharge, which can be partially explained by lowered rates of postoperative respiratory failure. Future randomized controlled trials should target driving pressure as a potential intervention to decrease nonhome discharge.

RéSUMé: OBJECTIF: Évaluer si la ventilation peropératoire utilisant une pression motrice plus faible diminue le risque de congé hors domicile. MéTHODE: Nous avons réalisé une étude de cohorte historique de patients âgés de ≥ 60 ans vivant à la maison avant de bénéficier d'une chirurgie non cardiothoracique non urgente dans deux réseaux de soins de santé tertiaires du Massachusetts entre 2007 et 2018. Nous avons évalué l'association entre la pression motrice médiane pendant la ventilation mécanique peropératoire et le congé ailleurs qu'au domicile à l'aide d'une analyse de régression logistique multivariable, ajustée pour tenir compte des facteurs liés aux patients et à l'intervention. En fonction de l'association primaire, nous avons évalué la modification de l'effet par le risque initial des patients et la médiation par l'insuffisance respiratoire postopératoire. RéSULTATS: Sur les 87 407 patients inclus, 12 584 (14,4 %) ont reçu leur congé ailleurs qu'au domicile. Dans les analyses ajustées, une pression motrice plus faible était associée à un risque réduit de congé hors domicile (rapport de cotes ajusté [RCa], 0,88; intervalle de confiance [IC] à 95 %, 0,83 à 0,93, par diminution de 10 cm H2O; P < 0,001). Cette association a été amplifiée chez les patients présentant un risque initial élevé (RCa, 0,77; IC 95 %, 0,73 à 0,81, par diminution de 10 cm H2O, P-pour-interaction < 0,001). Les résultats ont été confirmés chez 19 518 patients appariés pour la compliance initiale de leur système respiratoire (RCa, 0,90; IC 95 %, 0,81 à 1,00; P = 0,04 pour des pressions motrices faibles [< 15 cm H2O] vs élevées [≥ 15 cm H2O]). Un risque plus faible d'insuffisance respiratoire a entraîné une association entre une faible pression motrice et un congé à l'extérieur du domicile (20,8 %; IC 95 %, 15,0 à 56,8 ; P < 0,001). CONCLUSION: La ventilation peropératoire maintenant une pression motrice plus faible a été associée à un risque plus faible de congé hors domicile, ce qui peut s'expliquer en partie par des taux réduits d'insuffisance respiratoire postopératoire. Les futures études randomisées contrôlées devraient cibler la pression motrice comme intervention potentielle pour réduire les congés hors domicile.

Association Between Intraoperative Dexamethasone and Postoperative Mortality in Patients Undergoing Oncologic Surgery: A Multicentric Cohort Study.

OBJECTIVE: We examined the effects of dexamethasone on postoperative mortality, recurrence-free survival, and side effects in patients undergoing oncologic operations. BACKGROUND: Dexamethasone prevents nausea and vomiting after anesthesia and may affect cancer proliferation. METHODS: A total of 30,561 adult patients undergoing solid cancer resection between 2005 and 2020 were included. Multivariable logistic regression was applied to investigate the effect of dexamethasone on 1-year mortality and recurrence-free survival. Effect modification by the cancer's potential for immunogenicity, defined as a recommendation for checkpoint inhibitor therapy based on the National Comprehensive Cancer Network guidelines, was investigated through interaction term analysis. Key safety endpoints were dexamethasone-associated risk of hyperglycemia >180 mg/dL within 24 hours and surgical site infections within 30 days after surgery. RESULTS: Dexamethasone was administered to 38.2% (11,666/30,561) of patients (6.5±2.3 mg). Overall, 3.2% (n=980/30,561) died and 15.4% (n=4718/30,561) experienced cancer recurrence within 1 year of the operation. Dexamethasone was associated with a -0.6% (95% confidence interval: -1.1, -0.2, P =0.007) 1-year mortality risk reduction [adjusted odds ratio (OR adj ): 0.79 (0.67, 0.94), P =0.009; hazard ratio=0.82 (0.69, 0.96), P =0.016] and higher odds of recurrence-free survival [OR adj : 1.28 (1.18, 1.39), P <0.001]. This effect was only present in patients with solid cancers who were defined as not to respond to checkpoint inhibitor therapy [OR adj : 0.70 (0.57, 0.87), P =0.001 vs OR adj : 1.13 (0.85, 1.50), P =0.40]. A high (>0.09 mg/kg) dose of dexamethasone increased the risk of postoperative hyperglycemia [OR adj : 1.55 (1.32, 1.82), P <0.001], but not for surgical site infections [OR adj : 0.84 (0.42, 1.71), P =0.63]. CONCLUSIONS: Dexamethasone is associated with decreased 1-year mortality and cancer recurrence in patients undergoing surgical resection of cancers that are not candidates for immune modulators. Dexamethasone increased the risk of postoperative hyperglycemia, however, no increase in surgical site infections was identified.

Comparison of the effects of sugammadex versus neostigmine for reversal of neuromuscular block on hospital costs of care.

BACKGROUND: Sugammadex reversal of neuromuscular block facilitates recovery of neuromuscular function after surgery, but the drug is expensive. We evaluated the effects of sugammadex on hospital costs of care. METHODS: We analysed 79 474 adult surgical patients who received neuromuscular blocking agents and reversal from two academic healthcare networks between 2016 and 2021 to calculate differences in direct costs. We matched our data with data from the Healthcare Cost and Utilization Project-National Inpatient Sample (HCUP-NIS) to calculate differences in total costs in US dollars. Perioperative risk profiles were defined based on ASA physical status and admission status (ambulatory surgery vs hospitalisation). RESULTS: Based on our registry data analysis, administration of sugammadex vs neostigmine was associated with lower direct costs (-1.3% lower costs; 95% confidence interval [CI], -0.5 to -2.2%; P=0.002). In the HCUP-NIS matched cohort, sugammadex use was associated with US$232 lower total costs (95% CI, -US$376 to -US$88; P=0.002). Subgroup analysis revealed that sugammadex was associated with US$1042 lower total costs (95% CI, -US$1198 to -US$884; P<0.001) in patients with lower risk. In contrast, sugammadex was associated with US$620 higher total costs (95% CI, US$377 to US$865; P<0.001) in patients with a higher risk (American Society of Anesthesiologists physical status ≥3 and preoperative hospitalisation). CONCLUSIONS: The effects of using sugammadex on costs of care depend on patient risk, defined based on comorbidities and admission status. We observed lower costs of care in patients with lower risk and higher costs of care in hospitalised surgical patients with severe comorbidities.

Residence near industrial complex and cancer incidence: A registry-based cohort of 1,022,637 participants with a follow-up of 21 years, Israel.

BACKGROUND: Industrial complex (IC) residence is associated with higher cancer incidence in adults and children. However, the effect on young adults and the residence duration are not well described. Since the beginning of the 20th century, the Haifa bay area (HBA) has a major IC area with petrochemical industry complex and many other industries. The objectives of the current study were to estimate the association between IC residence and cancer incidence and to evaluate the effect of the residence duration. METHODS: This study is a registry-based cohort (N = 1,022,637) with a follow-up of 21 years. Cox regression models were used to evaluate the associations (hazards ratios (HR) and its 95% confidence intervals (CIs)) between HBA residence and incidence of all cancer sites (n = 62,049) and for site-specific cancer types including: lung cancer (n = 5398), bladder cancer (n = 3790), breast cancer (n = 11,310), prostate cancer (n = 6389) skin cancer (n = 4651), pancreatic cancer (n = 2144) and colorectal cancer (n = 8675). We evaluated the effect of the duration of exposure as categories of 7 years for those with 15 years of follow-up. RESULTS: IC residence was associated with higher risk for all cancer sites (HR:1.09, 95% CI: 1.06-1.12), for site-specific cancer incidence including: lung cancer (HR:1.14, 95% CI: 1.04-1.23), bladder cancer (HR:1.11, 95% CI: 1.01-1.23), breast cancer (HR:1.04, 95% CI: 0.98-1.10), prostate cancer (HR:1.07, 95% CI: 0.99-1.16), skin cancer (HR:1.22, 95% CI: 1.12-1.33) and colorectal cancer (HR:1.10, 95%CI: 1.03-1.17). Similar risk was also observed among young adults (HR: 1.10, 95% CI: 1.00-1.20). In the analyses for the duration of exposure, IC residence was associated with higher risk for all cancer site for the longest residence duration (15-21 years: HR: 1.08, 95% CI: 1.04-1.13). CONCLUSIONS: Harmful associations were found between IC residence and incidence of all cancer sites and site-specific cancers types. Our findings add to the limited evidence of associations between IC residence and cancer in young adults.

Throwing out old dogma: time for introduction of universal VZV vaccination in the UK.

There has been a reticence to introduce universal varicella zoster virus (VZV) vaccines in the UK because of a theoretical concern of increased herpes zoster infections. However, this has not been borne out in real-world data. Here, I argue that, in reality, many parents are vaccinating their children privately and, thus, we do not know the degree of inequity that this creates. The fairest option going forward is to introduce universal VZV vaccination in the UK.

Theory-Driven, Multi-Stage Process to Develop a Culturally-Informed Anti-Stigma Intervention for Pregnant Women Living with HIV in Botswana.

Background and Objectives: Despite a well-established universal HIV diagnosis and treatment program, Botswana continues to face a high HIV prevalence, in large part due to persistent stigma, which particularly affects pregnant women and interferes with healthcare engagement. Tackling stigma as a fundamental cause of HIV disparities is an important but understudied aspect of current HIV interventions. Our multinational and multicultural team used a theory-driven, multi-stage iterative process to develop measures and interventions to first identify and then target the most culturally-salient aspects of stigma for mothers living with HIV in Botswana. This methodology report examines the stage-by-stage application of the "What Matters Most" (WMM) theory and lessons learned, sharing a replicable template for developing culturally-shaped anti-stigma interventions. Methods: First, we conducted initial qualitative work based on the WMM theory to identify key structural and cultural factors shaping stigma for women living with HIV in Botswana. Second, we developed a psychometrically validated scale measuring how "what matters most" contributes to and protects against stigma for this population. Third, we designed an anti-stigma intervention, "Mothers Moving towards Empowerment" (MME), centered on the local values identified using WMM theory that underly empowerment and motherhood by adapting a cognitive behavioral therapy (CBT)-informed, group-based, and peer-co-led anti-stigma intervention specifically for pregnant women living with HIV. Fourth, we conducted a pilot study of MME in which participants were allocated to two trial arms: intervention or treatment-as-usual control. Results: Our qualitative research identified that bearing and caring for children are capabilities essential to the concept of respected womanhood, which can be threatened by a real or perceived HIV diagnosis. These values informed the development and validation of a scale to measure these culturally-salient aspects of stigma for women living with HIV in Botswana. These findings further informed our intervention adaptation and pilot evaluation, in which the intervention group showed significant decreases in HIV stigma and depressive symptoms compared to the control group. Participants reported overcoming reluctance to disclose their HIV status to family, leading to improved social support. Conclusion and Global Health Implications: Previous studies have not utilized culturally-based approaches to assess, resist, and intervene with HIV-related stigma. By applying WMM in each stage, we identified cultural and gendered differences that enabled participants to resist HIV stigma. Focusing on these capabilities that enable full personhood, we developed an effective culturally-tailored anti-stigma intervention for pregnant women living with HIV in Botswana. This theory-driven, multi-stage approach can be replicated to achieve stigma reduction for other outcomes, populations, and contexts.

A pilot pragmatic trial of a "what matters most"-based intervention targeting intersectional stigma related to being pregnant and living with HIV in Botswana.

We conducted a pilot trial of an intervention targeting intersectional stigma related to being pregnant and living with HIV while promoting capabilities for achieving 'respected motherhood' ('what matters most') in Botswana. A pragmatic design allocated participants to the intervention (N = 44) group and the treatment-as-usual (N = 15) group. An intent-to-treat, difference-in-difference analysis found the intervention group had significant decreases in HIV stigma (d = - 1.20; 95% CI - 1.99, - 0.39) and depressive symptoms (d = - 1.96; 95% CI - 2.89, - 1.02) from baseline to 4-months postpartum. Some, albeit less pronounced, changes in intersectional stigma were observed, suggesting the importance of structural-level intervention components to reduce intersectional stigma.

"Residential greenness and site-specific cancer: A registry based cohort of 144,427 participants with a 21-years of follow-up, Tel-Aviv district, Israel".

BACKGROUND: Few longitudinal studies evaluated the beneficial associations between cumulative residential greenness and site-specific cancer. Our objective was to evaluate the associations between cumulative residential greenness exposure and site-specific cancer incidence (lung, bladder, breast, prostate, and skin cancer) within a registry-based cohort study. METHODS: This study was based on 144,427 participants who lived in the Tel Aviv district during 1995-2015. The residential greenness exposure was estimated for every participant, as the weighted mean residential greenness exposure, based on the mean Normalized Difference Vegetation Index (NDVI) in the residential area and the duration of the residence in this area. Cox regression models were used to evaluate the unadjusted and adjusted associations between exposure to greenness and cancer incidence during 1998-2015 (Hazard Ratios (HRs) and 95% Confidence Intervals (CIs)). Covariates included in adjusted models were selected based on prior knowledge and directed acyclic graphs. We imputed missing data and further sensitivity analyses were conducted. RESULTS: After adjustments, beneficial associations between exposure to greenness and cancer incidence were observed. An interquartile range (IQR) increase in NDVI was associated with a lower HRs for lung cancer (HRadj. = 0.75 95% CI: 0.66-0.85), bladder cancer (HRadj. = 0.71, 95% CI: 0.62-0.82), breast cancer (HRadj. = 0.81, 95% CI: 0.74-0.88), prostate cancer (HRadj. = 0.77, 95% CI: 0.70-0.86) and skin cancer (HRadj. = 0.78, 95% CI: 0.69-0.88). Generally, the patterns of associations were consistent between complete-case models and imputed models, when estimated for participants aged 16 years or 40 years and older at baseline, when stratified by area level socioeconomic status, when evaluated for non-movers participants and after further adjustment to social determinants of health. CONCLUSION: Residential greenness may reduce the risk for lung, bladder, breast, prostate, and skin cancers. If our observations will be replicated, it may present a useful avenue for public-health intervention to reduce cancer burden.

The Emerging Role of E3 Ubiquitin Ligase SMURF2 in the Regulation of Transcriptional Co-Repressor KAP1 in Untransformed and Cancer Cells and Tissues.

KAP1 is an essential nuclear factor acting as a scaffold for protein complexes repressing transcription. KAP1 plays fundamental role in normal and cancer cell biology, affecting cell proliferation, DNA damage response, genome integrity maintenance, migration and invasion, as well as anti-viral and immune response. Despite the foregoing, the mechanisms regulating KAP1 cellular abundance are poorly understood. In this study, we identified the E3 ubiquitin ligase SMURF2 as an important regulator of KAP1. We show that SMURF2 directly interacts with KAP1 and ubiquitinates it in vitro and in the cellular environment in a catalytically-dependent manner. Interestingly, while in the examined untransformed cells, SMURF2 mostly exerted a negative impact on KAP1 expression, a phenomenon that was also monitored in certain Smurf2-ablated mouse tissues, in tumor cells SMURF2 stabilized KAP1. This stabilization relied on the unaltered E3 ubiquitin ligase function of SMURF2. Further investigations showed that SMURF2 regulates KAP1 post-translationally, interfering with its proteasomal degradation. The conducted immunohistochemical studies showed that the reciprocal relationship between the expression of SMURF2 and KAP1 also exists in human normal and breast cancer tissues and suggested that this relationship may be disrupted by the carcinogenic process. Finally, through stratifying KAP1 interactome in cells expressing either SMURF2 wild-type or its E3 ligase-dead form, we demonstrate that SMURF2 has a profound impact on KAP1 protein-protein interactions and the associated functions, adding an additional layer in the SMURF2-mediated regulation of KAP1. Cumulatively, these findings uncover SMURF2 as a novel regulator of KAP1, governing its protein expression, interactions, and functions.

The E3 ubiquitin ligase SMURF2 stabilizes RNA editase ADAR1p110 and promotes its adenosine-to-inosine (A-to-I) editing function.

Epitranscriptomic changes in RNA catalyzed by the RNA-editing enzyme ADAR1 play an essential role in the regulation of diverse molecular and cellular processes, both under physiological conditions and in disease states, including cancer. Yet, despite a growing body of evidence pointing to ADAR1 as a potential therapeutic target, the mechanisms regulating its cellular abundance and activity, particularly of its constitutively expressed and ubiquitous form, ADAR1p110, are poorly understood. Here, we report the HECT-type E3 ubiquitin ligase SMURF2 as a pivotal regulator of ADAR1p110. We show that SMURF2, which is primarily known to promote the ubiquitin-mediated degradation of its protein substrates, protects ADAR1p110 from proteolysis and promotes its A-to-I editase activity in human and mouse cells and tissues. ADAR1p110's interactome analysis performed in human cells also showed a positive influence of SMURF2 on the stability and function of ADAR1p110. Mechanistically, we found that SMURF2 directly binds, ubiquitinates and stabilizes ADAR1p110 in an E3 ubiquitin ligase-dependent manner, through ADAR1p110 ubiquitination at lysine-744 (K744). Mutation of this residue to arginine (K744R), which is also associated with several human disorders, including dyschromatosis symmetrica hereditaria (DSH) and some types of cancer, abolished SMURF2-mediated protection of ADAR1p110 from both proteasomal and lysosomal degradation and inactivated ADAR1p110-mediated RNA editing. Our findings reveal a novel mechanism underlying the regulation of ADAR1 in mammalian cells and suggest SMURF2 as a key cellular factor influencing the protein abundance, interactions and functions of ADAR1p110.

Association Between Intraoperative Arterial Hypotension and Postoperative Delirium After Noncardiac Surgery: A Retrospective Multicenter Cohort Study.

BACKGROUND: It is unclear whether intraoperative arterial hypotension is associated with postoperative delirium. We hypothesized that intraoperative hypotension within a range frequently observed in clinical practice is associated with increased odds of delirium after surgery. METHODS: Adult noncardiac surgical patients undergoing general anesthesia at 2 academic medical centers between 2005 and 2017 were included in this retrospective cohort study. The primary exposure was intraoperative hypotension, defined as the cumulative duration of an intraoperative mean arterial pressure (MAP) <55 mm Hg, categorized into and short (<15 minutes; median [interquartile range {IQR}], 2 [1-4] minutes) and prolonged (≥15 minutes; median [IQR], 21 [17-31] minutes) durations of intraoperative hypotension. The primary outcome was a new diagnosis of delirium within 30 days after surgery. In secondary analyses, we assessed the association between a MAP decrease of >30% from baseline and postoperative delirium. Multivariable logistic regression adjusted for patient- and procedure-related factors, including demographics, comorbidities, and markers of procedural severity, was used. RESULTS: Among 316,717 included surgical patients, 2183 (0.7%) were diagnosed with delirium within 30 days after surgery; 41.7% and 2.6% of patients had a MAP <55 mm Hg for a short and a prolonged duration, respectively. A MAP <55 mm Hg was associated with postoperative delirium compared to no hypotension (short duration of MAP <55 mm Hg: adjusted odds ratio [ORadj], 1.22; 95% confidence interval [CI], 1.11-1.33; P < .001 and prolonged duration of MAP <55 mm Hg: ORadj, 1.57; 95% CI, 1.27-1.94; P < .001). Compared to a short duration of a MAP <55 mm Hg, a prolonged duration of a MAP <55 mm Hg was associated with greater odds of postoperative delirium (ORadj, 1.29; 95% CI, 1.05-1.58; P = .016). The association between intraoperative hypotension and postoperative delirium was duration-dependent (ORadj for every 10 cumulative minutes of MAP <55 mm Hg: 1.06; 95% CI, 1.02-1.09; P =.001) and magnified in patients who underwent surgeries of longer duration (P for interaction = .046; MAP <55 mm Hg versus no MAP <55 mm Hg in patients undergoing surgery of >3 hours: ORadj, 1.40; 95% CI, 1.23-1.61; P < .001). A MAP decrease of >30% from baseline was not associated with postoperative delirium compared to no hypotension, also when additionally adjusted for the cumulative duration of a MAP <55 mm Hg (short duration of MAP decrease >30%: ORadj, 1.13; 95% CI, 0.91-1.40; P = .262 and prolonged duration of MAP decrease >30%: ORadj, 1.19; 95% CI, 0.95-1.49; P = .141). CONCLUSIONS: In patients undergoing noncardiac surgery, a MAP <55 mm Hg was associated with a duration-dependent increase in odds of postoperative delirium. This association was magnified in patients who underwent surgery of long duration.

The Mid-Atlantic Centers for AIDS Research Consortium: Promoting HIV Science Through Regional Collaboration.

The Centers for AIDS Research (CFAR) program was established by the National Institutes of Health in 1988 to catalyze and support high-impact HIV research and to develop the next generation of HIV investigators at academic institutions throughout the United States. In 2014, the Penn CFAR, the Johns Hopkins University CFAR and the District of Columbia CFAR developed a partnership-the Mid-Atlantic CFAR Consortium (MACC)-to promote cross-CFAR scientific collaboration, mentoring, and communication and to address the regional HIV epidemic. Over the past 6 years, the creation of the MACC has resulted in a rich web of interconnectivity, which has fostered scientific collaboration through working groups on the black men who have sex with men (MSM) and Latinx regional HIV epidemics, joint peer-reviewed publications, and successful collaborative grant applications on topics ranging from HIV prevention in young MSM, transgender women, implementation science, and clinical epidemiology; supported developmental activities through the MACC Scholars program, cross-CFAR mentoring, joint symposia, cross-CFAR seminar participation, and keynote speakers; and promoted strategic communication through advisory committees, best practices consultations, and the social and behavioral science research network. The MACC has been highly impactful by promoting HIV science through regional collaboration, supporting a diverse network of scholars across three cities and focusing on the epidemic in underrepresented and marginalized communities. Lessons learned from this consortium may have implications for scientific research centers beyond the field of HIV.

The association of nitrous oxide on length of stay in the postanesthesia care unit: a retrospective observational study.

PURPOSE: To assess whether intraoperative use of nitrous oxide (N2O) as an adjunct to general anesthesia is associated with a shorter length of stay in the postanesthesia care unit (PACU). METHODS: We analyzed data from adult patients who underwent non-cardiothoracic surgery under general anesthesia between May 2008 and December 2018. We assessed the association between intraoperative low- and high-dose N2O and PACU length of stay. RESULTS: A total of 148,284 patients were included in the primary analysis. After adjusting for a priori defined confounders, a high dose of N2O significantly decreased PACU length of stay, with a calculated difference of -9.1 min (95% confidence interval [CI], -10.5 to -7.7; P < 0.001). Patients who received high-dose N2O had a lower incidence of both short- and prolonged-duration of intraoperative hypotension (adjusted odds ratio [aOR], 0.85; 95% CI, 0.83 to 0.88; P < 0.001 and aOR, 0.76; 95% CI, 0.73 to 0.80; P < 0.001, respectively) and received a lower total intraoperative vasopressor dose (-0.04 mg of norepinephrine equivalents; 95% CI, -0.06 to -0.01; P = 0.01). The effect of high-dose N2O on PACU length of stay was modified by surgical complexity (adjusted absolute difference: -26.1 min; 95% CI, -29.2 to -23.1; P < 0.001; P for interaction < 0.001), and most pronounced in patients who underwent complex surgery and received intraoperative antiemetic therapy (adjusted absolute difference: -38.9 min; 95% CI, -43.1 to -34.6; P < 0.001; P for interaction < 0.001). CONCLUSIONS: Nitrous oxide was dose-dependently associated with a decreased PACU length of stay. The effect was clinically relevant (> 30 min difference) in patients who underwent complex surgical procedures and received intraoperative antiemetic therapy.

RéSUMé: OBJECTIF: L'objectif de cette étude était de déterminer si l'utilisation peropératoire de protoxyde d'azote (N2O) en complément à l'anesthésie générale était associée à une durée de séjour écourtée en salle de réveil (SDR). MéTHODE: Nous avons analysé les données de patients adultes qui ont subi une chirurgie non cardiothoracique sous anesthésie générale entre mai 2008 et décembre 2018. Nous avons évalué l'association entre une faible dose et une dose élevée de N2O peropératoire et la durée du séjour en SDR. RéSULTATS: Au total, 148 284 patients ont été inclus dans notre analyse primaire. Après ajustement tenant compte des facteurs de confusion définis a priori, une dose élevée de N2O a considérablement écourté la durée du séjour en salle de réveil, avec une différence calculée de −9,1 min (intervalle de confiance [IC] à 95 %, −10,5 à −7,7 ; P < 0,001). Chez les patients ayant reçu une dose élevée de N2O, l'incidence d'hypotension peropératoire de courte ou plus longue durée était plus faible (rapport de cotes ajusté [RCA], 0,85; IC 95 %, 0,83 à 0,88; P < 0,001 et RCA, 0,76; IC 95 %, 0,73 à 0,80; P < 0,001, respectivement); en outre, ces patients ont reçu une dose totale de vasopresseurs peropératoires inférieure (−0,04 mg d'équivalents de norépinéphrine; IC 95 %, −0,06 à −0,01; P = 0,01). L'effet d'une dose élevée de N2O sur la durée du séjour en SDR a été modifié par la complexité de la chirurgie (différence absolue ajustée : −26,1 min; IC 95 %, −29,2 à −23,1; P < 0,001; P pour l'interaction < 0,001), et était le plus prononcé chez les patients ayant subi une chirurgie complexe et reçu un traitement antiémétique peropératoire (différence absolue ajustée : −38,9 min; IC 95 %, −43,1 à −34,6; P < 0,001; P pour l'interaction < 0,001). CONCLUSION: Le protoxyde d'azote a été associé de façon dose-dépendante à une réduction de la durée du séjour en SDR. L'effet était cliniquement pertinent (différence > 30 minutes) chez les patients qui subissaient des interventions chirurgicales complexes et recevaient un traitement antiémétique peropératoire.

Effect of Intraoperative Arterial Hypotension on the Risk of Perioperative Stroke After Noncardiac Surgery: A Retrospective Multicenter Cohort Study.

BACKGROUND: Intraoperative cerebral blood flow is mainly determined by cerebral perfusion pressure and cerebral autoregulation of vasomotor tone. About 1% of patients undergoing noncardiac surgery develop ischemic stroke. We hypothesized that intraoperative hypotension within a range frequently observed in clinical practice is associated with an increased risk of perioperative ischemic stroke within 7 days after surgery. METHODS: Adult noncardiac surgical patients undergoing general anesthesia at Beth Israel Deaconess Medical Center and Massachusetts General Hospital between 2005 and 2017 were included in this retrospective cohort study. The primary exposure was intraoperative hypotension, defined as a decrease in mean arterial pressure (MAP) below 55 mm Hg, categorized into no intraoperative hypotension, short (<15 minutes, median [interquartile range {IQR}], 2 minutes [1-5 minutes]) and prolonged (≥15 minutes, median [IQR], 21 minutes [17-31 minutes]) durations. The primary outcome was a new diagnosis of early perioperative ischemic stroke within 7 days after surgery. In secondary analyses, we assessed the effect of a MAP decrease by >30% from baseline on perioperative stroke. Analyses were adjusted for the preoperative STRoke After Surgery (STRAS) prediction score, work relative value units, and duration of surgery. RESULTS: Among 358,391 included patients, a total of 1553 (0.4%) experienced an early perioperative ischemic stroke. About 42% and 3% of patients had a MAP of below 55 mm Hg for a short and a prolonged duration, and 49% and 29% had a MAP decrease by >30% from baseline for a short and a prolonged duration, respectively. In an adjusted analysis, neither a MAP <55 mm Hg (short duration: adjusted odds ratio [ORadj], 0.95; 95% confidence interval [CI], 0.85-1.07; P = .417 and prolonged duration: ORadj, 1.18; 95% CI, 0.91-1.55; P = .220) nor a MAP decrease >30% (short duration: ORadj, 0.97; 95% CI, 0.67-1.42; P = .883 and prolonged duration: ORadj, 1.30; 95% CI, 0.89-1.90; P = .176) was associated with early perioperative stroke. A high a priori stroke risk quantified based on preoperatively available risk factors (STRAS prediction score) was associated with longer intraoperative hypotension (adjusted incidence rate ratio, 1.04; 95% CI, 1.04-1.05; P < .001 per 5 points of the STRAS prediction score). CONCLUSIONS: This study found no evidence to conclude that intraoperative hypotension within the range studied was associated with early perioperative stroke within 7 days after surgery. These findings emphasize the importance of perioperative cerebral blood flow autoregulation to prevent ischemic stroke.