Reducing broad-spectrum antibiotic use in intensive care unit between first and second waves of COVID-19 did not adversely affect mortality.

BACKGROUND: The COVID-19 pandemic increased the use of broad-spectrum antibiotics due to diagnostic uncertainty, particularly in critical care. Multi-professional communication became more difficult, weakening stewardship activities. AIM: To determine changes in bacterial co-/secondary infections and antibiotics used in COVID-19 patients in critical care, and mortality rates, between the first and second waves. METHODS: Prospective audit comparing bacterial co-/secondary infections and their treatment during the first two waves of the pandemic in a single-centre teaching hospital intensive care unit. Data on demographics, daily antibiotic use, clinical outcomes, and culture results in patients diagnosed with COVID-19 infection were collected over 11 months. FINDINGS: From March 9th, 2020 to September 2nd, 2020 (Wave 1), there were 156 patients and between September 3rd, 2020 and February 1st, 2021 (Wave 2) there were 235 patients with COVID-19 infection admitted to intensive care. No significant difference was seen in mortality or positive blood culture rates between the two waves. The proportion of patients receiving antimicrobial therapy (93.0% vs 81.7%; P < 0.01) and the duration of meropenem use (median (interquartile range): 5 (2-7) vs 3 (2-5) days; P = 0.01) was lower in Wave 2. However, the number of patients with respiratory isolates of Pseudomonas aeruginosa (4/156 vs 21/235; P < 0.01) and bacteraemia from a respiratory source (3/156 vs 20/235; P < 0.01) increased in Wave 2, associated with an outbreak of infection. There was no significant difference between waves with respect to isolation of other pathogens. CONCLUSION: Reduced broad-spectrum antimicrobial use in the second wave of COVID-19 compared with the first wave was not associated with significant change in mortality.

Phase separation in the itinerant metamagnetic transition of Sr4Ru3O10.

We have investigated the electronic transport properties of the triple-layered ruthenate Sr4Ru3O10. We observed surprising anomalous features near its itinerant metamagnetic transition, including ultrasharp magnetoresistivity steps, a nonmetallic temperature dependence in resistivity for upward field sweeps, and a resistivity drop in temperature dependence for downward field sweeps. These features suggest that the metamagnetic transition of Sr4Ru3O10 occurs via an electronic phase separation process with magnetic domain formation.

Solid state coordination chemistry of the copper(ii)-terpyridine/oxovanadium organophosphonate system: hydrothermal syntheses, structural characterization and magnetic properties.

The hydrothermal reactions of CuSO4.5H2O, Na3VO4, 2,2':6':2''-terpyridine (terpy), and the appropriate organophosphonate ligand yield a series of materials of the Cu(ii)-terpy/oxovanadium organophosphonate family. The complexes exhibit distinct structures spanning one-, two- and three-dimensions and exhibiting diverse oxovanadium building blocks. Thus, [{Cu(terpy)}(V2O4)(O3PPh)(HO3PPh)2] (1) is one-dimensional and constructed from binuclear units of corner-sharing V(v) square pyramids. While [{Cu(terpy)}VO(O3PCH2PO3)] (2), [{Cu(terpy)}2(V4O10)(O3PCH2CH2PO3)] (3), and [{Cu(terpy)}(V2O4){O3P(CH2)3PO3}].2.5H(2)O (4.2.5H2O) are similarly one-dimensional, the V/O structural components consist of isolated V(iv) square pyramids, tetranuclear V(v) units of three tetrahedra and one square pyramid in a corner-sharing arrangement, and isolated V(v) tetrahedra and square pyramids, respectively. The second propylenediphosphonate derivative, [{Cu(terpy)}(V2O4){O3P(CH2)3PO3}] (5) is three-dimensional and exhibits isolated V(v) tetrahedra as the vanadate component. The two-dimensional structure of [{Cu(terpy)(H2O)}(V3O6){O3P(CH2)4PO3}] (6) is mixed valence with isolated V(iv) square pyramids and binuclear units of corner-sharing V(v) tetrahedra providing the V/O substructures.

Breath sound changes associated with malpositioned endotracheal tubes.

Endotracheal tubes (ETTs) are used to establish airway access in patients with ventilatory failure and during general anaesthesia. Tube malpositioning can compromise respiratory function and can be associated with increased morbidity and mortality. Clinical assessment of ETT position normally involves chest auscultation, which is highly skill-dependent and can be misleading. The objective of this pilot study was to investigate breath sound changes associated with ETT malpositioning. Breath sounds were acquired in six human subjects over each hemithorax and over the epigastrium for tracheal, bronchial and oesophageal intubations. When the ETT was in the oesophagus, the acoustic energy ratio between epigastrium and chest surface increased in all subjects (p < 0.04). In addition, ETT placement in the right mainstem bronchus decreased the acoustic energy ratio between the left and right hemithoraxes in all subjects (p < 0.04). A baseline measurement of this energy ratio was needed for bronchial intubation identification. However, using this ratio after bandpass filtering (200-500 Hz) did not require a baseline value, which would increase the utility of this method for initial ETT placement. These results suggest that computerised analysis of breath sounds may be useful for assessment of ETT positioning. More studies are needed to test the feasibility of this approach further.

Solid state coordination chemistry: structural consequences of variations in tether length in the oxovanadium-copper-bisterpy-[O3P(CH2)nPO3]4- system, n= 1-6 (bisterpy = 2,2':4',4'':2'',2'''-quarterpyridyl-6',6''-di-2-pyridine).

Hydrothermal reactions of Na3VO4, an appropriate Cu(II) source, bisterpy and an organodiphosphonate, H2O3P(CH2)nPO3H2 (n = 1-6) yielded a family of materials of the type [Cu2(bisterpy)]4+/VxOy(n-)/[O3P(CH2)nPO3]4-. This family of bimetallic oxides is characterized by an unusual structural diversity. The oxides [[Cu2(bisterpy)]V2O4[O3PCH2PO3H]2] (1), [[Cu2(bisterpy)(H2O)]VO2[O3P(CH2)3PO3][HO3P(CH2)3PO3H2]] (4) and [[Cu2(bisterpy)]V2O4[O3P(CH2)6PO3H]2].2H2O (7.2H2O) are one-dimensional, while [[Cu2(bisterpy)(H2O)2]V2O4[O3P(CH2)2PO3][HO3P(CH2)2PO3H]2] (2), [[Cu2(bisterpy)]V4O8[O3P(CH23PO3]2].4H2O (3.4H2O) and [[Cu2(bisterpy)]V2O4(OH)2[O3P(CH2)4PO3]].4H2O (5.4H2O) are two-dimensional. The V(IV) oxide [[Cu2(bisterpy)]V4O4[O3P(CH2)5PO3H]4].7.3H2O (6.7.3H2O) provides a relatively unusual example of a three-dimensional bimetallic oxide phosphonate. The structures reveal a variety of V/P/O substructures as building blocks.

Depth of insertion of the ProSeal laryngeal mask airway.

BACKGROUND: The depth of insertion of the ProSeal laryngeal mask airway (PLMA) is unknown. We measured depth of insertion in satisfactorily positioned PLMAs. METHODS: All women received size 4 masks and men size 5 masks. We measured the position of the integral bite block in relation to the upper incisors documented in patients over a 6-month period. Depth of insertion was scored by dividing the integral bite block into quarters. Satisfactory positioning of the ProSeal itself was determined by (i) positive 'suprasternal notch test', (ii) no venting via the drain tube during maximal lung inflation, and (iii) an unobstructed airway. RESULTS: We studied 274 patients (147 women and 127 men). The midway point of the bite block was proximal to the incisors (e.g. within the oropharynx) in 78% of women (95% CI 71-85%) and 92% of men (95% CI 87-97). The standard deviation for the depth distribution in women was 0.8 cm and for men was 1.0 cm. CONCLUSIONS: Usually most of the integral bite block lies within the oropharynx. It was never normal for the entire bite block to stick out of the mouth (4 SD from the mean for both men and women). The position of the integral bite block relative to the upper incisors gives valuable information during assessment of PLMA position.

Esophageal aspiration of air through the drain tube of the ProSeal laryngeal mask.

IMPLICATIONS: Two patients experienced partial upper airway obstruction while breathing spontaneously with the ProSeal laryngeal mask airway. This resulted in esophageal aspiration of air through the drain tube.

Pulmonary thromboembolism during liver transplantation: possible association with antifibrinolytic drugs and novel treatment options.

The authors describe two cases of massive intraoperative pulmonary thromboembolism resulting in cardiovascular collapse during liver transplantation. The potential role of antifibrinolytic drugs is discussed, along with the use of treatment modalities not previously applied in this setting.

The impact of renal dysfunction on aprotinin pharmacokinetics during cardiopulmonary bypass.

UNLABELLED: Aprotinin is a serine protease inhibitor that undergoes metabolism in the kidney. Because elimination is almost entirely renal, the clearance of aprotinin may be reduced in patients with renal insufficiency. Unfortunately, there are no data regarding aprotinin pharmacokinetics in cardiac surgical patients with renal insufficiency or end-stage renal disease (ESRD) undergoing cardiopulmonary bypass (CPB). We, therefore, determined the clearance (ApCl) and elimination half-life (T1/2) of aprotinin in 26 cardiac surgical patients with normal and abnormal renal function (creatinine clearance [CrCl] 0-122 mL/min) undergoing CPB. Subjects were given a 2 million kallikrein inhibiting unit (KIU) initial dose of aprotinin, followed by a 0.25 million KIU/h infusion. No aprotinin was added to the pump prime. Plasma aprotinin concentrations were sampled at 30 min after completion of the loading dose, 30 and 60 min after the onset of CPB, at the end of CPB, and at 8, 24, and 32 h after completion of the loading dose. ApCl was directly related and the elimination T1/2 inversely related to CrCl (r = 0.75 and 0.42, respectively). In patients with a CrCl >50 mL/min, the T1/2 and ApCl were 7.8 h and 53 mL/min, respectively, compared with 19.9 h and 25 mL/min (P < 0.05, P < 0.002, respectively) for patients with ESRD. In conclusion, ApCl is reduced, and T1/2 is prolonged in patients with renal insufficiency or ESRD undergoing CPB. Dosing modifications may be necessary for patients with abnormal renal function undergoing cardiac surgery. IMPLICATIONS: Because aprotinin is metabolized and eliminated in the kidney, its clearance may be reduced in patients with renal insufficiency. Our data suggest that aprotinin clearance is reduced, and aprotinin half-lives are prolonged in patients with renal insufficiency undergoing CPB. Dosing modification may therefore be indicated when aprotinin is administered to these patients for cardiac surgery.

N-Substituted 2-(2,6-dinitrophenylamino)propanamides: novel prodrugs that release a primary amine via nitroreduction and intramolecular cyclization.

A series of N-dinitrophenylamino acid amides [(4-CONHZ-2, 6-diNO2Ph)N(R)C(X,Y)CONHPhOMe] were prepared as potential bioreductive prodrugs and reduced radiolytically to study their rates of subsequent intramolecular cyclization. Compounds bearing a free NH group (R = H) underwent rapid cyclization in neutral aqueous buffers (t1/2 < 1 min) following 4-electron reduction, with the generation of a N-hydroxydihydroquinoxalinone and concomitant release of 4-methoxyaniline. Amine release from analogous N-methyl analogues (R = Me) was relatively slow. These results are consistent with intramolecular cyclization of a monohydroxylamine intermediate. The high rates of cyclization/extrusion by these very electron-deficient hydroxylamines suggest that the process is greatly accelerated by the presence of an H-bonding "conformational lock" between the anilino NH group and the adjacent o-nitro group (Kirk and Cohen, 1972). Changes in the phenylcarboxamide side chain or in C-methylation in the linking chain had little effect on the rate of cyclization. The model compounds had 1-electron reduction potentials in the range appropriate for cellular reduction (-373 mV for a measured example) and appeared suitable for development as prodrugs that release amine-based effectors following enzymic or radiolytic reduction. Prodrug examples containing 4-aminoaniline mustard and 5-amino-1-(chloromethyl)benz[e]indoline alkylating units were evaluated but were not activated efficiently by cellular nitroreductases. However, cell killing by the radiation-induced reduction of the latter prodrug was demonstrated.

The effect of pH on the inhibition of bacterial growth by physiological concentrations of butyric acid: implications for neonates fed on suckled milk.

Butyric acid is released from milk by pre-intestinal lipases during suckling. It is also known to inhibit bacterial growth. To investigate whether butyric acid may be a significant factor in controlling bacterial growth in the stomach of pre-weaned animals, the ability of butyric acid to inhibit growth of selected bacteria was tested over physiological ranges of pH and butyric acid concentrations. Six enteric and environmental strains of bacteria were used: two strains of Escherichia coli, Klebsiella pneumoniae, Enterococcus faecium, Enterococcus faecalis, and Enterococcus casseliflavus. At pH 4.5 and 5.0, the growth of all organisms was significantly inhibited in the presence of butyrate, and in some cases growth was completely arrested. At pH 6.0, butyric acid did not affect bacterial growth until the concentration reached 40 mM. The maximum concentration of butyric acid available in cow's milk after incubation with pre-gastric lipase is approximately 16 mM, which would be sufficient to prevent growth of the organisms tested at pH values occurring in the stomach. Therefore, butyric acid inhibition of bacterial growth may explain in part, the role of pre-intestinal lipases in young animals' natural defenses against bacteria in ingested food prior to weaning.

Comparative mutational spectra of the nitrogen mustard chlorambucil and its half-mustard analogue in Chinese hamster AS52 cells.

Nitrogen mustards play an important role in current cancer chemotherapy. The most effective antitumour agents are those carrying two alkylating functions, probably through their ability to form interstrand cross-links in DNA. Such lesions appear to create more of a block in DNA replication and are more difficult to repair than are most monoadducts. Although there were early reports that monofunctional drugs were more mutagenic than the bifunctional drugs, this has not been formally proved using structurally related drugs in a mutagenicity assay capable of detecting a range of different events. We have studied both the mutagenic potency and spectrum of events caused by treatment with the clinical agent, chlorambucil, compared with its half-mustard analogue, in Chinese hamster ovary (CHO)-AS52 cells. Although both drugs caused comparable increases in mutation frequency at doses killing 90% of cells (from around 9x10-6 to around 9x10-5 mutant cells), the nature of events differed significantly between the drugs. By far the majority of mutations caused by the half-mustard were transversion mutations, and almost all of these could be interpreted in relation to the DNA adducts that are known to be formed. In contrast, the majority of chlorambucil-induced mutations were major deletions, and point mutations were only identified from a few clones. Parallel micronucleus assays verified that chlorambucil has a stronger ability to break chromosomes than the half-mustard. These two drugs are thought to form similar monoadducts, but only the full mustard can form interstrand cross-links. The data suggest that DNA cross-links, although only a minor fraction of the total lesions, dominate the mutagenic spectrum and lead to gross changes at the chromosome level that can not be readily associated with individual lesions produced by the drug.

Mono- and dysfunctional nitrogen mustard analogues of the DNA minor groove binder pibenzimol. Synthesis, cytotoxicity and interaction with DNA.

Two series of mono- and dysfunctional aniline mustards linked to a bisbenzimidazole minor groove binder have been prepared using a new method (polyphosphate ester-mediated direct coupling of appropriate mustard acids with a preformed advanced phenylenediamine intermediate). As the linker chain attaching the mustard was lengthened the binding site size of the compounds to calf thymus DNA remained essentially constant at 2.6 nucleotides, but reversible binding strength declined by a factor of 2. Analogues with longer linker chains alkylated DNA much more rapidly than those with shorter chains, consistent with the electronic factors. The short chain analogues also failed to alkylate a 120 bp HindIII to Bg/II fragment of the gpt gene, as measured by gel electrophoresis cleavage assays. The longer chain analogues (both mono- and dysfunctional mustards) showed patterns of DNA alkylation that varied with chain length. In particular, while most compounds showed substantial N7 alkylation at many guanine residues, the analogue with a (CH2)3 linker chain showed strong alkylation at adenine sites in poly-AT regions. For the longer chain analogues, the bifunctional mustards were substantially (10- to 20-fold) more cytotoxic than the corresponding monofunctional analogues.

Hydrolysis characteristics of bovine milk fat and monoacid triglycerides mediated by pregastric lipase from goats and kids.

Commercial extracts from oro-pharyngeal tissues of goats and kids have been used as the source of pregastric lipase and have been processed to yield partially purified samples of the primary pregastric lipase. The activity of these lipases against tributyrylglycerol has been determined over a range of pH and temperatures. Optimum pH conditions for pregastric lipase ranged from pH 5.6 to 6.5 for goats and from pH 5.5 to 6.2 for kids, respectively; the optimum temperature ranged from 43 to 60 degrees C. Optima for kid lipase extended slightly below pH 5.5 and higher than 60 degrees C; which were the limits of the test conditions. The enzymes were also used as catalysts for the hydrolysis of monoacid triglycerides (C4:0 to C12:0) at 40 degrees C and pH 6.5; activity was maximum against tributyrylglycerol (C4:0). Values for the Michaelis-Menten constant, increased as carbon chain length of the carboxylic moiety on the triglycerides increased, but values were identical for pregastric lipases of both goats and kids. Anhydrous milk fat was hydrolyzed by the commercial extracts of pregastric lipases of goats and kids, and the resulting profiles for free fatty acids were very similar to one another and to the corresponding profile for a commercial sample of Parmesan cheese. There appear to be no significant differences in activity between the enzyme preparations from goats and kids.