Oral decitabine/cedazuridine versus intravenous decitabine for acute myeloid leukaemia: A randomised, crossover, registration, pharmacokinetics study.

This study compared decitabine exposure when administered IV (DEC-IV) at a dose of 20 mg/m2 for 5-days with orally administered decitabine with cedazuridine (DEC-C), as well as the clinical efficacy and safety of DEC-C in patients with acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy. In all, 89 patients were randomised 1:1 to DEC-IV or oral DEC-C (days 1-5 in a 28-day treatment cycle), followed by 5 days of the other formulation in the next treatment cycle. All patients received oral DEC-C for subsequent treatment cycles until treatment discontinuation. Equivalent systemic decitabine exposures were demonstrated (5-day area under the curve ratio between the two decitabine formulations of 99.64 [90% confidence interval 91.23%, 108.80%]). Demethylation rates also were similar (≤1.1% difference). Median overall survival (OS), clinical response and safety profile with oral DEC-C were consistent with those previously observed with DEC-IV. Next-generation sequencing was performed to identify molecular abnormalities that impact OS and TP53 mutations were associated with a poor outcome. These findings support the use of oral DEC-C in patients with AML.

Association of chronic poststernotomy pain and health-related quality of life: a prospective cohort study.

PURPOSE: Chronic poststernotomy pain (CPSP) after cardiac surgery is multifactorial and impacts patient recovery. We aimed to evaluate the association between CPSP severity and health-related quality of life at six months after cardiac surgery. METHODS: This was a single-centre prospective cohort study of patients who underwent cardiac surgery with median sternotomy between September 2020 and March 2021. Telephone interviews were conducted at six and 12 months postoperatively using the Short Form McGill Pain Questionnaire and the EQ-5D-5L. Strength of correlation was described using Spearman's correlation coefficient. Multivariable regression analysis was used to account for confounding variables. RESULTS: A total of 252 patients responded to the six-month interview (response rate, 65%). The mean (standard deviation) age of respondents was 65 (13) yr. Twenty-nine percent of respondents (72/252) reported CPSP at six months, and 14% (41/252) reported more than mild pain (score ≥ 2/5). At 12 months, of the 89% (64/72) patients who responded, 47% (30/64) still reported pain. The strength of the correlation between pain scores and EQ-5D-5L was weak (Spearman's correlation coefficient, -0.3). Risk factors for CPSP at six months included higher pain score on postoperative day 1, history of chronic pain prior to surgery, and history of depression. Intraoperative infusion of dexmedetomidine or ketamine was associated with a reduced risk of CPSP at six months. CONCLUSION: Chronic poststernotomy pain still affects patient recovery at six and 12 months after cardiac surgery. The severity of that pain is poorly correlated with patients' quality of life. STUDY REGISTRATION: www.osf.io ( https://osf.io/52rsw ); registered 14 May 2022.

RéSUMé: OBJECTIF: La douleur chronique post-sternotomie (DCPS) après une chirurgie cardiaque est multifactorielle et a un impact sur le rétablissement des patient·es. Nous avons cherché à évaluer l'association entre la sévérité de la DCPS et la qualité de vie liée à la santé six mois après la chirurgie cardiaque. MéTHODE: Il s'agissait d'une étude de cohorte prospective monocentrique portant sur des patient·es ayant bénéficié d'une chirurgie cardiaque avec sternotomie médiane entre septembre 2020 et mars 2021. Des entrevues téléphoniques ont été menées à six et 12 mois après l'opération en se servant du questionnaire abrégé de McGill sur la douleur et de l'EQ-5D-5L. La force de corrélation a été décrite à l'aide du coefficient de corrélation de Spearman. Une analyse de régression multivariée a été utilisée pour tenir compte des variables confondantes. RéSULTATS: Au total, 252 patient·es ont répondu à l'entrevue à six mois (taux de réponse de 65 %). L'âge moyen (écart type) des répondant·es était de 65 (13) ans. Vingt-neuf pour cent des personnes répondantes (72/252) ont déclaré avoir été atteintes de DCPS à six mois, et 14 % (41/252) ont signalé une douleur plus que légère (score ≥ 2/5). À 12 mois, sur les 89 % (64/72) personnes ayant répondu, 47 % (30/64) signalaient encore de la douleur. La force de la corrélation entre les scores de douleur et l'EQ-5D-5L était faible (coefficient de corrélation de Spearman, −0,3). Les facteurs de risque de DCPS à six mois comprenaient un score de douleur plus élevé au jour 1 postopératoire, des antécédents de douleur chronique avant la chirurgie et des antécédents de dépression. Une perfusion peropératoire de dexmédétomidine ou de kétamine a été associée à une réduction du risque de DCPS à six mois. CONCLUSION: La douleur chronique post-sternotomie affecte toujours le rétablissement des patient·es six et 12 mois après la chirurgie cardiaque. La sévérité de cette douleur est faiblement corrélée à la qualité de vie des patient·es. ENREGISTREMENT DE L'éTUDE: www.osf.io ( https://osf.io/52rsw ); enregistrée le 14 mai 2022.

An Integrated Photonic Biosensing Platform for Pathogen Detection in Aquaculture.

Aquaculture is expected to play a vital role in solving the challenge of sustainably providing the growing world population with healthy and nutritious food. Pathogen outbreaks are a major risk for the sector, so early detection and a timely response are crucial. This can be enabled by monitoring the pathogen levels in aquaculture facilities. This paper describes a photonic biosensing platform based on silicon nitride waveguide technology with integrated active components, which could be used for such applications. Compared to the state of the art, the current system presents improvements in terms of miniaturization of the Photonic Integrated Circuit (PIC) and the development of wafer-level processes for hybrid integration of active components and for material-selective chemical and biological surface modification. Furthermore, scalable processes for integrating the PIC in a microfluidic cartridge were developed, as well as a prototype desktop readout instrument. Three bacterial aquaculture pathogens (Aeromonas salmonicida, Vagococcus salmoninarum, and Yersinia ruckeri) were selected for assay development. DNA biomarkers were identified, corresponding primer-probe sets designed, and qPCR assays developed. The biomarker for Aeromonas was also detected using the hybrid PIC platform. This is the first successful demonstration of biosensing on the hybrid PIC platform.

Allogeneic haematopoietic cell transplant in patients with relapsed/refractory anaplastic large cell lymphoma.

The prognosis of relapsed/refractory (R/R) anaplastic large cell lymphoma (ALCL) is poor. Large studies evaluating outcomes of allogeneic haematopoietic cell transplantation (allo-HCT) in systemic R/R ALCL are not available. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we evaluated outcomes of 182 adults (aged ≥18 years) with R/R ALCL undergoing allo-HCT between 2008 and 2019. Non-relapse mortality (NRM), disease relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) were modelled using Cox proportional hazards models. The median (range) follow-up of survivors was 62 (3-148) months. The 1-year NRM was 18%. The 5-year REL, PFS and OS were 32%, 41% and 56% respectively. On multivariable regression analysis African American race (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.6-4.8; p < 0.001) and refractory disease at allo-HCT (HR 3.2, 95% CI 1.6-6.2; p < 0.001) were predictive of inferior OS. Similarly, African-American race (HR 2.1, 95% CI 1.3-3.4; p = 0.003), other minority race (HR 2.5, 95% CI 1.2-5.3; p = 0.02) and refractory disease (HR 2.2, 95% CI 1.2-4.3; p = 0.01) were predictive of inferior PFS. These data, demonstrate that allo-HCT can result in durable disease control in a sizable proportion of patients with R/R ALCL. Refractory disease and racial minority status predicted inferior allo-HCT outcomes. Whether the inferior outcomes of racial minorities with R/R ALCL after allo-HCT are driven by differences in disease biology or disparities in post allo-HCT care, or both, requires further investigation.

Overcoming Energy Transfer for the Metallophotoredox Catalyzed Decarboxylative Alkenylation between Alkylcarboxylic Acids and Enol Triflates.

Herein we report on the decarboxylative alkenylation between alkyl carboxylic acids and enol triflates. The reaction is mediated by a dual catalytic nickel and iridium system, operating under visible light irradiation. Two competing catalytic pathways, from the excited state iridium photocatalyst, are identified. One is energy transfer from the excited state, resulting in formation of an undesired enol ester. The desired pathway involves electron transfer, resulting in decarboxylation to ultimately give the target product. The use of a highly oxidizing iridium photocatalyst is essential to control the reactivity. A diverse array of enol triflates and alkyl carboxylic acids are investigated, providing both scope and limitations of the presented methodology.

Heterocyclic [9]Helicenes Exhibiting Bright Circularly Polarized Luminescence.

We describe a concise synthetic strategy for the preparation of heterocyclic [9]helicenes and a simple preparative-scale protocol for the optical resolution of the resulting M- and P-enantiomers. The helicenes were characterized by single-crystal X-ray diffraction along with a range of spectroscopic and computational techniques. A fluorescence quantum yield of up to 65 % was observed, and the chiroptical properties of both M- and P-helicenes revealed large dissymmetry factors. The circularly polarized luminescence brightness reaches up to 17 M-1 cm-1 , as measured experimentally and verified computationally, which makes this the highest circularly polarized luminescence brightness among heterocyclic helicenes. We describe how chiroptical properties (both circular dichroism and circularly polarized luminescence) can be described and predicted using quantum chemical calculations. The synthetic approach also reveals by-products that originate from internal oxidation reactions, presumably mediated by the close proximity of the π-surfaces in the helicene structure.

Sound localisation of low- and high-frequency sounds in cochlear implant users with single-sided deafness.

OBJECTIVE: Localisation of low- and high-frequency sounds in single-sided deaf cochlear implant users was investigated using noise stimuli designed to mitigate monaural localisation cues. DESIGN: Within subject design. Sound source localisation was tested in the horizontal plane using an array of seven loudspeakers along the azimuthal angle span from -90° to +90°. Stimuli were broadband noise and high- and low-frequency noise. STUDY SAMPLE: Twelve adult subjects with single-sided deafness participated in the study. All had normal hearing in the healthy ear and were supplied with a cochlear implant (CI) in their deaf ear. RESULTS: With broadband noise, the mean angular localisation error was 39° in aided condition as compared to a median angular error of 83.6° when the speech processor was not worn. For high-frequency noise, the median angular error was 30° and for low-frequency noise, it was 46° in the CI-aided condition. CONCLUSIONS: Single-sided deaf CI users show the best sound localisation for high-frequency sounds. This supports the view that interaural level differences are dominant for sound localisation in these listeners. Nonetheless, a limited ability to localise low-frequency sounds was observed, which may be based on the supportive perception of interaural time differences.

Development and internal validation of a multivariable risk prediction model for severe rebound pain after foot and ankle surgery involving single-shot popliteal sciatic nerve block.

BACKGROUND: Rebound pain occurs after up to 50% of ambulatory surgeries involving regional anaesthesia. To assist with risk stratification, we developed a model to predict severe rebound pain after foot and ankle surgery involving single-shot popliteal sciatic nerve block. METHODS: After ethics approval, we performed a single-centre retrospective cohort study. Patients undergoing lower limb surgery with popliteal sciatic nerve block from January 2016 to November 2019 were included. Exclusion criteria were uncontrolled pain in the PACU, use of a perineural catheter, or loss to follow-up. We developed and internally validated a multivariable logistic regression model for severe rebound pain, defined as transition from well-controlled pain in the PACU (numerical rating scale [NRS] 3 or less) to severe pain (NRS ≥7) within 48 h. A priori predictors were age, sex, surgery type, planned admission, local anaesthetic type, dexamethasone use, and intraoperative anaesthesia type. Model performance was evaluated using area under the receiver operating characteristic curve (AUROC), Nagelkerke's R2, scaled Brier score, and calibration slope. RESULTS: The cohort included 1365 patients (mean [standard deviation] age: 50 [16] yr). The primary outcome was abstracted in 1311 (96%) patients, with severe rebound pain in 652 (50%). Internal validation revealed poor model performance, with AUROC 0.632 (95% confidence interval [CI]: 0.602-0.661; bootstrap optimisation 0.021), Nagelkerke's R2 0.063, and scaled Brier score 0.047. Calibration slope was 0.832 (95% CI: 0.623-1.041). CONCLUSIONS: We show that a multivariable risk prediction model developed using routinely collected clinical data had poor predictive performance for severe rebound pain after foot and ankle surgery. Prospective studies involving other patient-related predictors are needed. CLINICAL TRIAL REGISTRATION: NCT05018104.

Exposed water ice on the nucleus of comet 67P/Churyumov-Gerasimenko.

Although water vapour is the main species observed in the coma of comet 67P/Churyumov-Gerasimenko and water is the major constituent of cometary nuclei, limited evidence for exposed water-ice regions on the surface of the nucleus has been found so far. The absence of large regions of exposed water ice seems a common finding on the surfaces of many of the comets observed so far. The nucleus of 67P/Churyumov-Gerasimenko appears to be fairly uniformly coated with dark, dehydrated, refractory and organic-rich material. Here we report the identification at infrared wavelengths of water ice on two debris falls in the Imhotep region of the nucleus. The ice has been exposed on the walls of elevated structures and at the base of the walls. A quantitative derivation of the abundance of ice in these regions indicates the presence of millimetre-sized pure water-ice grains, considerably larger than in all previous observations. Although micrometre-sized water-ice grains are the usual result of vapour recondensation in ice-free layers, the occurrence of millimetre-sized grains of pure ice as observed in the Imhotep debris falls is best explained by grain growth by vapour diffusion in ice-rich layers, or by sintering. As a consequence of these processes, the nucleus can develop an extended and complex coating in which the outer dehydrated crust is superimposed on layers enriched in water ice. The stratigraphy observed on 67P/Churyumov-Gerasimenko is therefore the result of evolutionary processes affecting the uppermost metres of the nucleus and does not necessarily require a global layering to have occurred at the time of the comet's formation.

Noise in the operating room during induction of anesthesia: impact of a quality improvement initiative.

PURPOSE: Noise in the operating room (OR) is common and associated with negative effects on anesthesiologists, surgeons, and patient outcomes. Induction of anesthesia is among the loudest perioperative periods. Despite its critical nature, there is little data on noise levels during induction, associated patient and anesthesiologist satisfaction, and the effects of noise reduction strategies. METHODS: We conducted a two-part prospective interventional quality improvement project on the care of adult patients receiving general anesthesia for elective noncardiac surgery. For part A, we measured average and peak noise (dB[A]) levels during anesthesia induction in N = 100 cases and administered a satisfaction questionnaire to anesthesiologists. We then applied a multidisciplinary educational program to OR personnel on active noise reduction strategies and subsequently collected data during N = 109 cases in a post-intervention phase. For part B, we administered satisfaction questionnaires to N = 100 patients pre- vs postintervention, respectively. RESULTS: Median [interquartile range] noise levels throughout induction were 66.0 [62.5-68.6] dB(A) preintervention vs 63.5 [60.1-65.4] dB[A] post-intervention (Hodges-Lehmann estimator of the difference, - 2.7 dB[A]; 95% confidence interval [CI], - 4.0 to - 1.5; P < 0.001). Peak noise levels during induction were 87.3 [84.0-90.5] dB(A) preintervention and 86.2 [81.8-89.3] dB(A) postintervention (Hodges-Lehmann estimator of the difference, - 1.8 dB[A]; 95% CI, - 3.3 to - 0.3; P = 0.02). Noise-related anesthesiologist satisfaction postintervention was significantly improved in multiple domains, including assessment of noise having distracted anesthesiologists. Patient satisfaction was high pre-intervention and did not significantly improve further. CONCLUSION: In this quality improvement project, average noise levels during induction of anesthesia, anesthesiologist satisfaction, and anesthesiologists' perceived ability to perform were improved following a multidisciplinary educational program on noise reduction in the OR. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT04204785); registered 19 December 2019.

RéSUMé: OBJECTIF: Le bruit en salle d'opération (SOP) est fréquent et associé à des effets négatifs sur les anesthésiologistes, les chirurgiens et les issues des patients. L'induction de l'anesthésie est l'une des périodes périopératoires les plus bruyantes. Malgré sa nature critique, il existe peu de données sur les niveaux sonores pendant l'induction, la satisfaction des patients et des anesthésiologistes qui y est reliée, et les effets des stratégies de réduction du bruit. MéTHODE: Nous avons mené un projet prospectif et interventionnel, en deux parties, d'amélioration de la qualité sur les soins aux patients adultes recevant une anesthésie générale pour une chirurgie non cardiaque non urgente. Dans le cadre de la première partie A, nous avons mesuré les niveaux de bruit moyen et maximaux (dB[A]) pendant l'induction de l'anesthésie dans n = 100 cas et administré un questionnaire de satisfaction aux anesthésiologistes. Nous avons ensuite appliqué un programme de formation multidisciplinaire au personnel de la salle d'opération sur les stratégies de réduction active du bruit et avons ensuite recueilli des données pour n = 109 cas dans une phase post-intervention. Pour la deuxième partie B, nous avons administré des questionnaires de satisfaction à n = 100 patients pré- vs post-intervention, respectivement. RéSULTATS: Les niveaux de bruit médians [écart interquartile] tout au long de l'induction étaient de 66,0 [62,5­68,6] dB(A) avant l'intervention vs 63,5 [60,1­65,4] dB[A] après l'intervention (estimateur de Hodges-Lehmann, − 2,7 dB[A]; intervalle de confiance [IC] 95 %, − 4,0 à − 1,5; P < 0,001). Les niveaux maximaux de bruit pendant l'induction étaient de 87,3 [84,0­90,5] dB(A) avant l'intervention et de 86,2 [81,8­89,3] dB(A) après l'intervention (estimateur de Hodges-Lehmann, − 1,8 dB[A]; IC 95 %, − 3,3 à − 0,3; P = 0,02). La satisfaction des anesthésiologistes par rapport au bruit après l'intervention a été considérablement améliorée dans de nombreux domaines, y compris l'évaluation du bruit ayant distrait les anesthésiologistes. La satisfaction des patients était élevée avant l'intervention et ne s'est pas améliorée de manière significative. CONCLUSION: Dans ce projet d'amélioration de la qualité, les niveaux de bruit moyens lors de l'induction de l'anesthésie, la satisfaction des anesthésiologistes et la capacité perçue des anesthésiologistes à réaliser leurs tâches ont été améliorés à la suite d'un programme de formation multidisciplinaire sur la réduction du bruit en salle d'opération. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT04204785); enregistrée le 19 décembre 2019.

Opioid dispensing after Cesarean delivery in British Columbia: a historical cohort analysis from 2004 to 2019.

PURPOSE: To describe postdischarge opioid dispensing after Cesarean delivery (CD) in 49 hospitals in British Columbia (BC) and assess opportunities for opioid stewardship. METHODS: Using the BC Ministry of Health's Hospital Discharge Abstract Database, we linked 135,725 CDs performed in 2004-2016 and 30,919 CDs performed in 2017-2019 (length of stay ≤ four days) by deidentified Personal Health Numbers to data on medications dispensed from all BC community pharmacies (PharmaNet). We excluded patients with cancer and those to whom opioids have been dispensed in the year before. We measured trends in annual percentages of patients dispensed opioids within seven days (opioid rate), with 95% confidence intervals (CIs), stratified by hospital and opioid type, adjusted for length of stay, and for autocorrelation within hospital using generalized linear modeling. RESULTS: The opioid dispensation rate dropped from 31% (95% CI, 30 to 33) in 2004 to 16% (95% CI, 15 to 17) in 2016, where it remained through 2019. Five hospitals showed steep reductions from over 40% to under 10% within two to three years, but in most hospitals the opioid dispensation rate decreased slowly-11 had little reduction and three showed increases. Codeine dispensing dropped from 31% in 2004-2008 by 4% per year, while tramadol and hydromorphone dispensing rose. After 2015, rates were stable (hydromorphone, 8%; tramadol, 6%; codeine, 3%; and oxycodone, 0.5%). CONCLUSION: After Health Canada's 2008 warning against codeine use by breastfeeding mothers, post-CD opioid dispensing declined disjointedly across BC hospitals. Rates did not decrease further after the opioid overdose epidemic was declared a public health emergency in BC in 2016. The present study highlights opportunities for quality improvement and opioid stewardship through monitoring using administrative databases.

RéSUMé: OBJECTIF: Décrire la délivrance d'opioïdes après le congé après un accouchement par césarienne dans 49 hôpitaux de la Colombie-Britannique (C.-B.) et évaluer les occasions de régulation des opioïdes. MéTHODE: À l'aide de la base de données sur les congés des patients du ministère de la Santé de la Colombie-Britannique, nous avons relié 135 725 accouchements par césarienne réalisés en 2004-2016 et 30 919 accouchements par césarienne réalisés en 2017-2019 (durée de séjour ≤ quatre jours) en utilisant les numéros de carte santé personnels dépersonnalisés aux données sur les médicaments délivrés par toutes les pharmacies communautaires de la Colombie-Britannique (PharmaNet). Nous avons exclu les patientes atteintes de cancer et celles à qui des opioïdes avaient été délivrés l'année précédente. À l'aide d'une modélisation linéaire généralisée, nous avons mesuré les tendances en pourcentages annuels de patientes ayant reçu des opioïdes dans les sept jours (taux d'opioïdes), avec des intervalles de confiance (IC) à 95 %, stratifiés par hôpital et par type d'opioïdes, ajustés en fonction de la durée de séjour et des autocorrélations entre des taux de chaque hôpital. RéSULTATS: Le taux de délivrance d'opioïdes est passé de 31 % (IC 95 %, 30 à 33) en 2004 à 16 % (IC 95 %, 15 à 17) en 2016, où il est resté jusqu'en 2019. Cinq hôpitaux ont montré des réductions importantes, passant de plus de 40 % à moins de 10 % en deux à trois ans, mais dans la plupart des hôpitaux, le taux de délivrance d'opioïdes a diminué lentement ­ 11 ont affiché une faible réduction et trois ont montré des augmentations. La délivrance de codéine a diminué de 4 % par année, à partir de 31 % en 2004-2008, tandis que la délivrance de tramadol et d'hydromorphone a augmenté. Après 2015, les taux étaient stables (hydromorphone, 8 %; tramadol, 6 %; codéine, 3 %; et oxycodone, 0,5 %). CONCLUSION: Suite à la mise en garde de Santé Canada en 2008 contre la consommation de codéine par les mères qui allaitent, la délivrance d'opioïdes post-césarienne a diminué de façon inconstante dans les hôpitaux de Colombie-Britannique. Les taux n'ont pas diminué davantage après que l'épidémie de surdose d'opioïdes a été déclarée urgence de santé publique en Colombie-Britannique en 2016. La présente étude met en évidence les possibilités d'amélioration de la qualité et de régulation des opioïdes en procédant à une surveillance via les bases de données administratives.

Trends in opioid dispensing after common abdominal and orthopedic surgery procedures in British Columbia: a retrospective cohort analysis.

PURPOSE: Postdischarge opioid prescriptions are reportedly much higher in Canada than in other countries. To assess potentially contributing factors, we examined trends after abdominal and orthopedic surgeries in British Columbia (BC). METHODS: Using the BC Ministry of Health's databases on physician billings, hospital discharge abstracts, and medication dispensations in community pharmacies for the period 2003-2016, we assembled a cohort of 263,056 patients who received laparoscopic appendectomy (LA, 11%), laparoscopic cholecystectomy (LC, 30%), open inguinal or femoral hernia repair (IHR, 20%), total hip arthroplasty (THA, 18%), or total knee arthroplasty (TKA, 22%). Adjusting for covariates using generalized linear modeling, we measured trends in percentages of patients dispensed opioids postdischarge (opioid rate) within 30 days after surgery, by surgery type, opioid type, prior use, surgeon, and trends in morphine milligram equivalents of first dispensations (MME) with 95% confidence intervals (CI). RESULTS: Opioid dispensation rates rose steadily. Mean annual increases were 1.7% in LA; 1.3% in LC; 0.8% in IHR; 0.9% in THA; and 0.8% in TKA. By 2016, rates were 69% in LA; 76% in LC; 81% in IHR; 88% in THA; and 94% in TKA. Codeine dispensations fell 2.4% (abdominal) and 3.1% (orthopedic) per year while tramadol dispensations increased 3.6% (abdominal) and 1.7% (orthopedic). Hydromorphone dispensations increased 2.9% per year (orthopedic); oxycodone was level at 22% between 2007 and 2014, but then fell. The mean MME rose 8 mg⋅yr-1 (95% CI, 7 to 9) (abdominal) and 61 mg⋅yr-1 (95% CI, 58 to 64) (orthopedic). Variation in rates was greater among abdominal than orthopedic surgeons. CONCLUSION: Rising opioid dispensation rates, together with shifts to prescribing higher MME opioids, doubled MME per patient in first dispensations postdischarge after abdominal or orthopedic surgery from 2003 to 2016 in BC.

RéSUMé: OBJECTIF: Les ordonnances d'opioïdes après le congé seraient beaucoup plus élevées au Canada que dans d'autres pays. Afin d'évaluer les facteurs contributifs potentiels, nous avons examiné les tendances après les chirurgies abdominales et orthopédiques en Colombie-Britannique (C.-B.). MéTHODE: En utilisant les bases de données du ministère de la Santé de la Colombie-Britannique de facturation des médecins, les résumés des congés d'hôpital et les délivrances de médicaments dans les pharmacies communautaires pour la période 2003-2016, nous avons regroupé une cohorte de 263 056 patients ayant bénéficié d'une appendicectomie par laparoscopie (AL, 11 %), d'une cholécystectomie par laparoscopie (CL, 30 %), d'une réparation ouverte de hernie inguinale ou fémorale (RHI, 20 %), d'une arthroplastie totale de la hanche (ATH, 18 %) ou d'une arthroplastie totale du genou (ATG, 22 %). En tenant compte des covariables à l'aide d'une modélisation linéaire généralisée, nous avons mesuré les tendances dans les pourcentages de patients ayant reçu des opioïdes après leur congé (taux de délivrance d'opioïdes) dans les 30 jours suivant leur chirurgie, par type de chirurgie, type d'opioïde, utilisation antérieure, chirurgien et tendances des équivalents de morphine en milligrammes (EMM) des premières délivrances avec des intervalles de confiance (IC) à 95 %. RéSULTATS: Les taux de délivrance d'opioïdes ont augmenté de manière constante. Les augmentations annuelles moyennes étaient de 1,7 % pour les AL, 1,3 % pour les CL, 0,8 % pour les RHI, 0,9 % pour les ATH, et 0,8 % pour les ATG. En 2016, les taux étaient de 69 % pour les AL, 76 % pour les CL, 81 % pour les RHI, 88 % pour les ATH, et 94 % pour les ATG. Les dispenses de codéine ont chuté de 2,4 % (chirurgie abdominale) et de 3,1 % (chirurgie orthopédique) par année, tandis que les délivrances de tramadol ont augmenté de 3,6 % (chirurgie abdominale) et de 1,7 % (chirurgie orthopédique). Les délivrances d'hydromorphone ont augmenté de 2,9 % par année (orthopédie); l'oxycodone était à 22 % entre 2007 et 2014, mais a ensuite diminué. Les EMM moyens ont augmenté de 8 mg·an-1 (IC 95 %, 7 à 9) (chirurgie abdominale) et de 61 mg·an-1 (IC 95 %, 58 à 64) (chirurgie orthopédique). La variation des taux était plus importante parmi les chirurgiens abdominaux que chez les chirurgiens orthopédistes. CONCLUSION: L'augmentation des taux de délivrance d'opioïdes, ainsi que le passage à une prescription d'opioïdes plus élevés en EMM, ont doublé les EMM par patient dans les premières délivrances après leur congé après une chirurgie abdominale ou orthopédique de 2003 à 2016 en Colombie-Britannique.

Electronic Materials: An Antiaromatic Propeller Made from the Four-Fold Fusion of Tetraoxa[8]circulene and Perylene Diimides.

The synthesis of an antiaromatic tetraoxa[8]circulene annulated with four perylene diimides (PDI), giving a dynamic non-planar π-conjugated system, is described. The molecule contains 32 aromatic rings surrounding one formally antiaromatic planarized cyclooctatetraene (COT). The intense absorption (ϵ=3.35×105  M-1 cm-1 in CH2 Cl2 ) and emission bands are assigned to internal charge-transfer transitions in the combined PDI-circulene π-system. The spectroscopic data is supported by density functional theory calculations, and nuclear independent chemical shift calculation indicate that the antiaromatic COT has increased aromaticity in the reduced state. Electrochemical studies show that the compound can reversibly reach the tetra- and octa-anionic states by reduction of the four PDI units, and the deca-anionic state by reduction of the central COT ring. The material functions effectively in bulk hetero junction solar cells as a non-fullerene acceptor, reaching a power conversion efficiency of 6.4 %.

Chirality Amplified: Long, Discrete Helicene Nanoribbons.

Here we report the synthesis of two polyhelicene frameworks consisting, from end-to-end, of 18 and 24 fused benzene rings. The latter exhibits the largest electronic circular dichroism in the visible spectrum of any molecule. These shape-persistent helical nanoribbons incorporate multiple helicenes, a class of contorted polycyclic aromatic molecules consisting of ortho-annulated rings. These conjugated, chiral molecules have interesting chemical, biological, and chiroptical properties; however, there are very few helicenes with extraordinary chiroptical response over a broad range of the visible spectrum-a key criterion for applications such as chiral optoelectronics. In this report, we show that coupling the polyhelicene framework with multiple perylene-diimide subunits elicits a significant chiroptic response. Notably, the molar circular dichroism increases faster than the absorptivity of these molecules as their helical axis lengthens. Computational analysis reveals that the greatly amplified circular dichroism arises from exciton-like interactions between the perylene-diimide and the helicene moieties. We predict that even greater chiroptic enhancement will result from further axial elongation of these nanoribbons, which can be readily enabled via the iterative synthetic method presented herein.

Triggering G-Quadruplex Conformation Switching with [7]Helicenes.

The dynamic interplay between two types of chiral structures; fully conjugated racemic hetero[7]helicenes and DNA strands prone to fold into G-quadruplex structures is described. Both the [7]helicenes and the G-quadruplex DNA structures exist in more than one conformation in solution. We show that the structures interact with and stabilise each other, mutually amplifying and stabilising certain conformations at increased temperatures. The [7]helicene ligands L1 and L2 stabilise the parallel conformation of k-ras significantly, whereas hybrid (K+ ) and antiparallel (Na+ ) h-telo G-quadruplexes are stabilised upon conformational switching into altered G-quadruplex conformations. Both L1 and L2 induce parallel G-quadruplexes from hybrid structures (K+ ) and L1 induces hybrid G-quadruplexes from antiparallel conformations (Na+ ). Enantioselective binding of one helicene enantiomer is observed for helicene ligand L2, and VTCD melting experiments are used to estimate the racemisation barrier of the helicene.

Dianthracenylazatrioxa[8]circulene: Synthesis, Characterization and Application in OLEDs.

A soluble, green-blue fluorescent, π-extended azatrioxa[8]circulene was synthesized by oxidative condensation of a 3,6-dihydroxycarbazole and 1,4-anthraquinone by using benzofuran scaffolding. This is the first circulene to incorporate anthracene within its carbon framework. Solvent-dependent fluorescence and bright green electroluminescence accompanied by excimer emission are the key optical properties of this material. The presence of sliding π-stacked columns in the single crystal of dianthracenylazatrioxa[8]circulene is found to cause a very high electron-hopping rate, thus making this material a promising n-type organic semiconductor with an electron mobility predicted to be around 2.26 cm2 V-1 s-1 . The best organic light-emitting diode (OLED) device based on the dianthracenylazatrioxa[8]circulene fluorescent emitter has a brightness of around 16 000 Cd m-2 and an external quantum efficiency of 3.3 %. Quantum dot-based OLEDs were fabricated by using dianthracenylazatrioxa[8]circulene as a host matrix material.

A new hypertonic saline assay for analgesic screening in mice: effects of animal strain, sex, and diurnal phase.

PURPOSE: There exists a pressing need for the identification of novel analgesics. We recently reported on a new preclinical assay for rapid analgesic screening based on intraplantar (i.pl.) injection of 10% hypertonic saline (HS) in female outbred (CD-1) mice. Herein, we characterized the HS assay's performance in inbred (C57BL/6) mice, sensitivity to sex differences, and effects of diurnal rhythm phase. METHODS: In randomized, controlled, blinded in vivo animal experiments, we studied nociceptive responses induced by i.pl. HS in C57BL/6 (vs CD-1) mice of both sexes (n = 240) and determined diurnal rhythm phase effects in female animals. We established the HS assay's sensitivity to morphine by constructing dose-response curves and calculating half-maximal inhibitory doses (ID50s). RESULTS: The injection of i.pl. HS produced nociceptive (licking and biting) responses in all C57BL/6 mice tested. In both C57BL/6 and CD-1 mice, the mean (95% confidence interval [CI]) response magnitudes were greater in females vs males (C57BL/6: 87 sec [64 to 110] vs 45 sec [29 to 61]; difference in means, 42 sec; 95% CI, 17 to 68; P < 0.001; n = 10/group; CD-1: 110 sec [95 to 126] vs 53 sec [32 to 74]; difference in means, 57 sec; 95% CI, 34 to 79; P < 0.001; n = 10/group). The mean (95% CI) nociceptive responses were greater at 24:00 hr than at 12:00 hr in C57BL/6 mice (64 sec [40 to 88] vs 37 sec [24 to 51]; difference in means, 27 sec; 95% CI, 7 to 47; P = 0.007; n = 10/group), but not in CD-1 mice (P = 0.97). Intravenous morphine dose-dependently attenuated nociceptive responses of both C57BL/6 and CD-1 mice (ID50, 0.6 and 2.5 mg·kg-1, respectively; P = 0.41). CONCLUSION: These findings in inbred and outbred mice solidify the utility of the HS assay as an effective, rapid, robust, and versatile preclinical tool for analgesic screening.

RéSUMé: OBJECTIF: Il existe un besoin impérieux d'identification de nouveaux analgésiques. Nous avons récemment publié les conclusions d'un nouveau test préclinique portant sur le dépistage analgésique rapide basé sur l'injection intraplantaire (i.pl.) d'une solution saline hypertonique à 10 % (HS) chez des souris femelles croisées (CD-1). Dans notre présente étude, nous avons caractérisé la performance du test de HS chez des souris consanguines (C57BL/6), la sensibilité aux différences de sexe, et les effets des phases de rythme diurne. MéTHODE: Dans le cadre d'expériences animales in vivo en aveugle randomisées contrôlées, nous avons étudié les réponses nociceptives induites par une i.pl. de HS chez des souris C57BL/6 (vs CD-1) des deux sexes (n = 240) et déterminé les effets des phases du rythme diurne chez les animaux femelles. Nous avons établi la sensibilité du test HS à la morphine en construisant des courbes de dose-réponse et en calculant des doses inhibitrices semi-maximales (DI50). RéSULTATS: L'injection i.pl. de HS a produit des réponses nociceptives (léchage et morsure) chez toutes les souris C57BL/6 testées. Chez les souris C57BL/6 et CD-1, les magnitudes de réponse moyenne [intervalle de confiance (IC) 95 %] étaient plus élevées chez les femelles que chez les mâles (C57BL/6 : 87 [64 à 110] vs 45 [29 à 61] sec; différence de moyennes, 42 sec; IC 95 %, 17 à 68; P < 0,001; n = 10/groupe; CD-1: 110 [95 à 126] vs 53 [32 à 74] sec; différence de moyennes, 57 sec; IC 95 %, 34 à 79; P < 0,001; n = 10/groupe). Les réponses nociceptives moyennes [IC 95 %] étaient plus importantes à minuit (24 h) qu'à midi (12 h) chez les souris C57BL/6 (64 [40 à 88] sec vs 37 [24 à 51] sec; différence de moyennes, 27 sec; IC 95 %, 7 à 47; P = 0,007; n = 10/groupe), mais pas chez les souris CD-1 (P = 0,97). La morphine intraveineuse a atténué de façon dose-dépendante les réponses nociceptives chez les souris C57BL/6 et CD-1 (DI50, 0,6 et 2,5 mg·kg−1, respectivement; P = 0,41). CONCLUSION: Ces résultats chez les souris croisées et consanguines appuient l'utilité du test de HS comme un outil préclinique efficace, rapide, robuste et polyvalent pour le dépistage analgésique.

A Fully Conjugated Planar Heterocyclic [9]Circulene.

Fully aromatic [n]circulenes have only been known to encompass up to eight aromatic rings (n = 8), with no reports of endeavors in the synthesis of higher-order analogues (n > 8). Herein we present the first [9]circulene, formally a diazatrioxa[9]circulene, along with a tetrahydro-diazatetraoxa[10]circulene. The key transformation, for construction of the macrocyclic framework, is a simple high-yielding dimerizing condensation between 3,6-dihydroxycarbazole and glyoxal. Single crystal X-ray analysis reveals the [9]circulene to be perfectly planar and containing elongated benzene rings, which is induced by strain to accommodate planarity. Alternating bond lengths in the solid state indicate contribution from a [9]radialene resonance structure in the [9]circulene π-system. The central nonaromatic rings of both circulenes have paratropic ring currents, as evident by nucleus independent chemical shift (NICS) and anisotropy of the induced current density (ACID) calculations, which can be attributed to induced paratropicity from the surrounding aromatic rings.

Compressing a Non-Planar Aromatic Heterocyclic [7]Helicene to a Planar Hetero[8]Circulene.

This work describes a synthetic approach where a non-planar aromatic heterocyclic [7]helicene is compressed to yield a hetero[8]circulene containing an inner antiaromatic cyclooctatetraene (COT) core. This [8]circulene consists of four benzene rings and four heterocyclic rings, and it is the first heterocyclic [8]circulene containing three different heteroatoms. The synthetic pathway proceeds via a the flattened dehydro-hetero[7]helicene, which is partially a helicene and partially a circulene: it is non-planar and helically chiral as helicenes, and contains a COT motif like [8]circulenes. The antiaromaticity of the COT core is confirmed by nucleus independent chemical shift (NICS) calculations. The planarization from a helically π-conjugated [7]helicene to a fully planar heterocyclic [8]circulene significantly alters the spectroscopic properties of the molecules. Post-functionalization of the [7]helicenes and the [8]circulenes by oxygenation of the thiophene rings to the corresponding thiophene-sulfones allows an almost complete fluorescence emission coverage of the visible region of the optical spectrum (400-700 nm).

A Single Prophylactic Dose of Ondansetron Given at Cessation of Postoperative Propofol Sedation Decreases Postoperative Nausea and Vomiting in Cardiac Surgery Patients: A Randomized Controlled Trial.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common occurrence after cardiac surgery. However, in contrast to other surgical populations, routine PONV prophylaxis is not a standard of care in cardiac surgery. We hypothesized that routine administration of a single prophylactic dose of ondansetron (4 mg) at the time of stopping postoperative propofol sedation before extubation in the cardiac surgery intensive care unit would decrease the incidence of PONV. METHODS: With institutional human ethics board approval and written informed consent, we conducted a randomized controlled trial in patients ≥19 years of age with no history of PONV undergoing elective or urgent cardiac surgery procedures requiring cardiopulmonary bypass. The primary outcome was the incidence of PONV in the first 24 hours postextubation, compared by the χ test. Secondary outcomes included the incidence and times to first dose of rescue antiemetic treatment administration, the incidence of headaches, and the incidence of ventricular arrhythmias. RESULTS: PONV within the first 24 hours postextubation occurred in 33 of 77 patients (43%) in the ondansetron group versus 50 of 82 patients (61%) in the placebo group (relative risk, 0.70 [95% confidence interval {CI}, 0.51-0.95]; absolute risk difference, -18% [95% CI, -33 to -2]; number needed to treat, 5.5 [95% CI, 3.0-58.4]; χ test, P = .022). Kaplan-Meier "survival" analysis of the times to first rescue antiemetic treatment administration over 24 hours indicated that patients in the ondansetron group fared better than those in the placebo group (log-rank [Mantel-Cox] test; P = .028). Overall, 32 of 77 patients (42%) in the ondansetron group received rescue antiemetic treatment over the first 24 hours postextubation versus 47 of 82 patients (57%) in the placebo group (relative risk, 0.73 [95% CI, 0.52-1.00]; absolute risk difference, -16% [95% CI, -31 to 1]); P = .047. There were no significant differences between the groups in the incidence of postoperative headache (ondansetron group, 5 of 77 patients [6%] versus placebo group, 4 of 82 patients [5%]; Fisher exact test; P = .740) or ventricular arrhythmias (ondansetron group, 2 of 77 patients [3%] versus placebo group, 4 of 82 patients [5%]; P = .68). CONCLUSIONS: These findings support the routine administration of ondansetron prophylaxis at the time of discontinuation of postoperative propofol sedation before extubation in patients following cardiac surgery. Further research is warranted to optimize PONV prophylaxis in cardiac surgery patients.