Background: This study aims to explore short-term changes following the introduction of alcohol restrictions (most notably 2 am to 3 am last drinks). We examined patterns of nightlife attendance, intoxication, and alcohol use among patrons shortly before and after restrictions were introduced in Fortitude Valley, Brisbane: the largest nighttime entertainment precinct of Queensland. Methods: Street-intercept patron interviews were conducted in Fortitude Valley in June (n = 497) and July (n = 562) 2016. A pre-post design was used to assess changes in time spent out drinking/partying prior to the interview, time of arrival in the precinct, pre-drinking, and blood alcohol concentration (BAC). Results: Regression models indicated that after the policy introduction, the proportion of people arriving at Fortitude Valley before 10:00 pm increased (OR = 1.38; 95% CI = 1.04, 1.82). Participants reported going out, on average, one hour earlier after the intervention (β = − 0.17; 95% CI = 0.11, 0.22). There was a decrease (RRR = 0.58; 95% CI = 0.43, 0.79) in the proportion of participants who had a high level of intoxication (BAC ≥0.10 g/dL) postintervention. No other significant differences were found. Conclusions: Earlier cessation of alcohol sales and stopping the sale of rapid intoxication drinks after midnight was associated with people arriving in Fortitude Valley earlier. Though legislative loopholes allowed some venues to continue trading to 5 am, the proportion of people in the precinct who were highly intoxicated decreased after the restriction. Further measurement will be required to determine whether the reduction has persisted.
Introduction: The hippocampus, a medial temporal lobe structure central to learning and memory, is particularly vulnerable in preterm-born neonates. To date, segmentation of the hippocampus for preterm-born neonates has not yet been performed early-in-life (shortly after birth when clinically stable). The present study focuses on the development and validation of an automatic segmentation protocol that is based on the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm to delineate the hippocampi of preterm neonates on their brain MRIs acquired at not only term-equivalent age but also early-in-life. Methods: First, we present a three-step manual segmentation protocol to delineate the hippocampus for preterm neonates and apply this protocol on 22 early-in-life and 22 term images. These manual segmentations are considered the gold standard in assessing the automatic segmentations. MAGeT-Brain, automatic hippocampal segmentation pipeline, requires only a small number of input atlases and reduces the registration and resampling errors by employing an intermediate template library. We assess the segmentation accuracy of MAGeT-Brain in three validation studies, evaluate the hippocampal growth fro m early-in-life to term-equivalent age, and study the effect of preterm birth on the hippocampal volume. The first experiment thoroughly validates MAGeT-Brain segmentation in three sets of 10-fold Monte Carlo cross-validation (MCCV) analyses with 187 different groups of input atlases and templates. The second experiment segments the neonatal hippocampi on 168 early-in-life and 154 term images and evaluates the hippocampal growth rate of 125 infants from early-in-life to term-equivalent age. The third experiment analyzes the effect of gestational age (GA) at birth on the average hippocampal volume at early-in-life and term-equivalent age using linear regression. Results: The final segmentations demonstrate that MAGeT-Brain consistently provides accurate segmentations in comparison to manually derived gold standards (mean Dice3s Kappa N 0.79 and Euclidean distance b1.3 mm be-tween centroids). Using this method, we demonstrate that the average volume of the hippocampus is significantly different (p b 0.0001) in early-in-life (621.8 mm3) and term-equivalent age (958.8 mm3). Using these differences,we generalize the hippocampal growth rate to 38.3 ± 11.7 mm3/week and 40.5 ± 12.9 mm3/week for the left and right hippocampi respectively. Not surprisingly, younger gestational age at birth is associated with smaller volumes of the hippocampi (p = 0.001). Conclusions: MAGeT-Brain is capable of segmenting hippocampi accurately in preterm neonates, even at early-in-life. Hippocampal asymmetry with a larger right side is demonstrated on early-in-life images, suggesting that this phenomenon has its onset in the 3rd trimester of gestation. Hippocampal volume assessed at the time of early-in-life and term-equivalent age is linearly associated with GA at birth, whereby smaller volumes are associated with earlier birth. ; Computations were performed on the SciNet supercomputer at the SciNet HPC Consortium. SciNet is funded by the Canada Foundation for Innovation under the auspices of Compute Canada, the Government of Ontario, Ontario Research Fund — Research Excellence and the University of Toronto. Supported by the Canadian Institutes of Health Research (CIHR) operating grants MOP-79262 (S.P.M.)and MOP-86489 (R.E.G.). SPM is currently the Bloorview Children's Hospital Chair in Pediatric Neuroscience and was supported by a Tier 2 Canada Research Chair in Neonatal Neuroscience, and Michael Smith Foundation for Health Research Scholar Award. MMC receives salary support from the Fonds de Recherche Québec Santé and is supported by CIHR, Natural Science s and Engineering Research Council of Canada, Weston Brain Institute, the Alzheimer's Society, Michael J Fox Foundation for Parkinson's Research, and Brain,Canada. REG holds a Senior Scientist salary award from the Child and Family Research Institute. We thank Dr. Margot Taylor, The Hospital for Sick Children (Toronto, Ontario), for the longitudinal MRI images presented in Fig. 1.
NADPH oxidase 4 (NOX4) regulates endothelial inflammation by producing hydrogen peroxide (H2O2) and to a lesser extent O2•-. The ratio of NOX4-derived H2O2 and O2•- can be altered by coenzyme Q (CoQ) mimics. Therefore, we hypothesize that cytochrome b5 reductase 3 (CYB5R3), a CoQ reductase abundant in vascular endothelial cells, regulates inflammatory activation. To examine endothelial CYB5R3 in vivo, we created tamoxifen-inducible endothelium-specific Cyb5r3 knockout mice (R3 KO). Radiotelemetry measurements of systolic blood pressure showed systemic hypotension in lipopolysaccharides (LPS) challenged mice, which was exacerbated in R3 KO mice. Meanwhile, LPS treatment caused greater endothelial dysfunction in R3 KO mice, evaluated by acetylcholine-induced vasodilation in the isolated aorta, accompanied by elevated mRNA expression of vascular adhesion molecule 1 (Vcam-1). Similarly, in cultured human aortic endothelial cells (HAEC), LPS and tumor necrosis factor α (TNF-α) induced VCAM-1 protein expression was enhanced by Cyb5r3 siRNA, which was ablated by silencing the Nox4 gene simultaneously. Moreover, super-resolution confocal microscopy indicated mitochondrial co-localization of CYB5R3 and NOX4 in HAECs. APEX2-based electron microscopy and proximity biotinylation also demonstrated CYB5R3's localization on the mitochondrial outer membrane and its interaction with NOX4, which was further confirmed by the proximity ligation assay. Notably, Cyb5r3 knockdown HAECs showed less total H2O2 but more mitochondrial O2•-. Using inactive or non-membrane bound active CYB5R3, we found that CYB5R3 activity and membrane translocation are needed for optimal generation of H2O2 by NOX4. Lastly, cells lacking the CoQ synthesizing enzyme COQ6 showed decreased NOX4-derived H2O2, indicating a requirement for endogenous CoQ in NOX4 activity. In conclusion, CYB5R3 mitigates endothelial inflammatory activation by assisting in NOX4-dependent H2O2 generation via CoQ. ; This work was supported by National Institutes of Health (NIH) R01 awards [R01 HL 133864 (A.C.S), R01 HL 128304 (A.C.S), R01 HL 149825 (A.C.S), R01 HL 153532 (A.C.S), R01 GM 125944 (F.J.S.), R01 DK 112854 (F.J.S.), 1S10OD021540-01 (Center for Biologic Imaging, University of Pittsburgh), 1S10RR019003-01 (Simon Watkins (S.W.)), 1S10RR025488-01 (S.W.), 1S10RR016236-01 (S.W)]. American Heart Association (AHA) [Established Investigator Award 19EIA34770095 (A.C.S.)], Post-doctoral Fellowship 19POST34410028 (S.Y.)]. American Society of Hematology (ASH) Minority Hematology Graduate Award (A.M.D-O.). Junta de Andalucía grant BIO-177 (P.N.), the FEDER Funding Program from the European Union and Spanish Ministry of Science, Innovation and Universities grant RED2018-102576-T (P.N.).
Background: Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction. Methods: This international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index 60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov, NCT04384926. Findings: Of eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16-30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio [HR] 0·81, 95% CI 0·77-0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50-0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notification rates, moderate lockdowns (HR 0·84, 95% CI 0·80-0·88; p<0·001), and full lockdowns (0·57, 0·54-0·60; p<0·001), remained independently associated with non-operation. Surgery beyond 12 weeks from diagnosis in patients without neoadjuvant therapy increased during lockdowns (374 [9·1%] of 4521 in light restrictions, 317 [10·4%] of 3646 in moderate lockdowns, 2001 [23·8%] of 11 827 in full lockdowns), although there were no differences in resectability rates observed with longer delays. Interpretation: Cancer surgery systems worldwide were fragile to lockdowns, with one in seven patients who were in regions with full lockdowns not undergoing planned surgery and experiencing longer preoperative delays. Although short-term oncological outcomes were not compromised in those selected for surgery, delays and non-operations might lead to long-term reductions in survival. During current and future periods of societal restriction, the resilience of elective surgery systems requires strengthening, which might include protected elective surgical pathways and long-term investment in surge capacity for acute care during public health emergencies to protect elective staff and services.