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HIV-1 reverse transcriptase can catalyze the addition of either azidothymidine monophosphate (AZTMP) or thymidine monophosphate (dTMP) to a primer strand opposite template adenosine bases. The ratio of incorporation of AZTMP to dTMP as catalyzed by HIV-1 reverse transcriptase has been determined to be 0.4 using an RNA-DNA duplex substrate prepared from oligonucleotides with sequences taken from the HIV-1 genome sequence. Slight variations are found for the incorporation ratio of the two nucleotides on other substrates. Substrates containing more than one adenosine in the single-stranded part of the template allow for more chances to incorporate AZTMP and less full-length product. Variations in the intensity of bands on an autoradiograph of a DNA sequencing gel corresponding to different positions of incorporation of AZTMP suggest that not all template adenosine positions offer the same level of discrimination against incorporation of AZTMP. A reverse transcriptase containing a set of four mutations (D67N, K70R, T215Y, K219Q) known to cause resistance to AZT in cell culture assays has a ratio of incorporation that is 0.77 +/- 0.03 times the ratio for the wild-type reverse transcriptase opposite one specific template adenosine. In contrast, a hybrid mutant containing the same four mutations that cause resistance to AZT and an additional mutation, Y181C, which by itself causes resistance to the non-nucleoside inhibitor L-697,661 [Sardana et al. (1992), J. Biol. Chem. 267, 17526-17530], has a ratio of incorporation that is 1.34 +/- 0.01 times that of the wild-type, indicating that the hybrid mutant enzyme is more susceptible to inhibition by AZTTP than the wild-type reverse transcriptase.(ABSTRACT TRUNCATED AT 250 WORDS)

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Background: The aim of this post hoc analysis of a large cohort study was to evaluate the association between night-time surgery and the occurrence of intraoperative adverse events (AEs) and postoperative pulmonary complications (PPCs). Methods: LAS VEGAS (Local Assessment of Ventilatory Management During General Anesthesia for Surgery) was a prospective international 1-week study that enrolled adult patients undergoing surgical procedures with general anaesthesia and mechanical ventilation in 146 hospitals across 29 countries. Surgeries were defined as occurring during 'daytime' when induction of anaesthesia was between 8:00 AM and 7:59 PM, and as 'night-time' when induction was between 8:00 PM and 7:59 AM. Results: Of 9861 included patients, 555 (5.6%) underwent surgery during night-time. The proportion of patients who developed intraoperative AEs was higher during night-time surgery in unmatched (43.6% vs 34.1%; P<0.001) and propensity-matched analyses (43.7% vs 36.8%; P¼0.029). PPCs also occurred more often in patients who underwent night-time surgery (14% vs 10%; P¼0.004) in an unmatched cohort analysis, although not in a propensity-matched analysis (13.8% vs 11.8%; P¼0.39). In a multivariable regression model, including patient characteristics and types of surgery and anaesthesia, night-time surgery was independently associated with a higher incidence of intraoperative AEs (odds ratio: 1.44; 95% confidence interval: 1.09e1.90; P¼0.01), but not with a higher incidence of PPCs (odds ratio: 1.32; 95% confidence interval: 0.89e1.90; P¼0.15). Conclusions: Intraoperative adverse events and postoperative pulmonary complications occurred more often in patients undergoing night-time surgery. Imbalances in patients' clinical characteristics, types of surgery, and intraoperative management at night-time partially explained the higher incidence of postoperative pulmonary complications, but not the higher incidence of adverse events. Clinical trial registration: NCT01601223.