A systematic review of pain outcomes reported by randomised trials of hip and knee arthroplasty.

It is difficult to pool results from randomised clinical trials that report different outcomes. We want to develop a core set of pain-related outcomes after total hip or knee arthroplasty, the first stage of which is to systematically review published outcomes. We searched PubMed, Embase and CENTRAL for relevant trials to January 2020. We identified 165 outcomes from 565 trials with 50,668 participants, which we categorised into six domains: pain; analgesic consumption; quality of care; adverse events; mobility; and patient-reported outcome measures. The outcome in each domain reported by most trials was: visual analogue score for pain, 401 (71%); morphine consumption, 212 (38%); length of hospital stay, 166 (29%); nausea or vomiting, 425 (75%); range of motion, 173 (31%); and patient satisfaction score, 181 (32%). A primary outcome was reported in 281 (50%) trials: 101 (18%) trials reported consumption of rescue analgesics and 95 (17%) trials reported pain. We plan to publish a consensus on outcomes that should be reported in postoperative pain trials after hip or knee arthroplasty.

Presence of the partner in the operating room during a category 1 cesarean section: a prospective explorative study.

BACKGROUND: Little information exists regarding attitudes related to the presence of the partner in the operation room (OR) during category 1 emergency cesarean section (cat. 1 CS). We investigated how cat. 1 CS under general anesthesia is experienced, both by partners present in the OR and those not. METHODS: An explorative prospective cohort trial, with qualitative elements, involving all cat. 1 CS in 2022 in two hospitals. At site 1 the partner was present in the OR during cat. 1 CS, whereas at site 2 the partner was not. Parents and staff answered questionnaires following each cat. 1 CS and semi-structured interviews with partners were held three months after surgery. Qualitative data were analyzed using content analysis. The primary outcome was the partner's answer to the question: "Would you have preferred not being present/being present in the OR?" respectively. RESULTS: Seventeen and eight cat. 1 CS occurred at each site respectively. All parents agreed to participate. No partners in site 1 would have preferred to wait outside, and all evaluated the experience very positively. Partners at site 2 also evaluated not being present positively. Overarching themes from the qualitative analysis were "Being the family witness" and "Experience of being the partner". Mothers and staff from site 1 were very positive about their partners' presence. CONCLUSION: Partners present in the OR during cat. 1 CS under general anesthesia evaluated this very positively. Most partners, who had not been present in the OR, also evaluated this positively. No partners had post-traumatic stress.

Antimicrobial disposition in pulmonary epithelial lining fluid of horses, part III. cefquinome.

Cefquinome concentrations, following intravenous and aerosol administration to horses, in pulmonary epithelial lining fluid (PELF) were examined and compared to plasma concentrations. Single dose of cefquinome sulphate (1 mg/kg) was administered intravenously to six horses followed by a single aerosol administration (225 mg) with a wash-out period of 14 days between treatments. After each drug administration, cefquinome concentrations in plasma and PELF, obtained by intrabronchial cotton swabs, were determined. After intravenous administration, cefquinome concentrations in plasma declined fast and were not detectable after 12 h. After aerosol administration, plasma concentrations were low or below limit of quantification (LOQ) during the entire sampling period. The degree of penetration of cefquinome into PELF after intravenous administration as described by the AUC(PELF) /AUC(plasma) ratio was 0.33. Following aerosol administration, cefquinome concentrations in PELF were high, but only detectable for 4 h. Based on AUC values, total cefquinome concentrations in PELF were one-third of total plasma concentrations after intravenous administration together with shorter time above Minimum Inhibitory Concentrations (T > MIC) in PELF, thus twice daily dosing may be required when treating lower airway infections in horses. Lower doses of cefquinome can be administered as aerosols providing high local drug concentrations in lung, but additional optimization of formulation is needed to improve distribution and persistence in lung.

Antimicrobial disposition in pulmonary epithelial lining fluid of horses. Part I. Sulfadiazine and trimethoprim.

Sulfadiazine (SDZ) and trimethoprim (TMP) concentrations were examined in plasma and pulmonary epithelial lining fluid (PELF), following intravenous and oral administration and compared to minimum inhibitory concentrations (MICs) of common bacterial isolates from equine lower airway infections. SDZ/TMP (25/5 mg/kg) was administered intravenously, intragastric or per os to fed horses, and blood samples were collected before and 11 times, over 24 h, after administration. PELF samples were collected via a tampon device four times after drug administration and analysed for drug concentrations. Additionally, MICs of SDZ and TMP alone and in combination were determined in a selection of clinical respiratory isolates. Bioavailability was 74% for SDZ and 46% for TMP after paste administration in fed horses. The degree of penetration of SDZ and TMP into PELF, as described by AUC(PELF) /AUC(plasma) ratios, was 0.68 and 0.72, respectively, after intravenous administration. After oral administration, the degree of penetration for SDZ and TMP was 0.92 and 0.46, respectively. MIC measurements using SDZ/TMP ratios of 5:1 and 10:1 did not affect the interpretation of the results. The results indicate that clinically relevant drug concentrations of mainly TMP are difficult to maintain in PELF, especially after oral administration of SDZ/TMP.

Antimicrobial disposition in pulmonary epithelial lining fluid of horses, part II. Doxycycline.

Doxycycline concentrations, following two types of oral administration to horses, in pulmonary epithelial lining fluid (PELF) were examined and compared to plasma concentrations. The oral bioavailability was estimated from plasma concentrations achieved after an intravenous study in two horses. Doxycycline (10 mg/kg) was administered either intragastric or as topdressing to nonfasted horses. Blood samples were collected for drug analysis, before and 11 times after administration during 24 h. PELF samples were collected by a tampon device four times after drug administration and analysed for doxycycline concentrations. Another two horses received doxycycline intravenously at a dose of 3 mg/kg and plasma was taken 14 times during a 24- h period. The oral bioavailability of doxycycline was calculated to 17% after intragastric administration and 6% after topdressing administration in nonfasted horses. The degree of penetration of doxycycline into PELF, as described by AUC(PELF) /AUC(plasma) ratios, was 0.87 after intragastric administration. The results indicate that clinically relevant doxycycline concentrations are possible to maintain in PELF after intragastric administration. Furthermore, if bioavailability could be enhanced for per os administration, doxycycline might be a valuable drug for the treatment of lower airway infections in horses.

Creating leadership collectives for sustainability transformations.

Enduring sustainability challenges requires a new model of collective leadership that embraces critical reflection, inclusivity and care. Leadership collectives can support a move in academia from metrics to merits, from a focus on career to care, and enact a shift from disciplinary to inter- and trans-disciplinary research. Academic organisations need to reorient their training programs, work ethics and reward systems to encourage collective excellence and to allow space for future leaders to develop and enact a radically re-imagined vision of how to lead as a collective with care for people and the planet. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11625-021-00909-y.

Optimal Timing for Laparoscopic Cholecystectomy After Endoscopic Retrograde Cholangiopancreatography: A Systematic Review.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography followed by laparoscopic cholecystectomy is often used as definitive treatment for common bile duct stones. The aim of this study was to investigate the optimal time interval between endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy. MATERIALS AND METHODS: PubMed and Embase were searched for studies comparing different time delays between endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy. Observational studies and randomized controlled trials were included. Primary outcome was conversion rate from laparoscopic to open cholecystectomy and secondary outcomes were complications, mortality, operating time, and length of stay. RESULTS: A total of 14 studies with a total of 1930 patients were included. The pooled estimate revealed an increase from a 4.2% conversion rate when laparoscopic cholecystectomy was performed within 24 h of endoscopic retrograde cholangiopancreatography to 7.6% for 24-72 h delay to 12.3% when performed within 2 weeks, to 12.3% for 2-6 weeks, and to a 14% conversion rate when operation was delayed more than 6 weeks. CONCLUSION: According to this systematic review, it is preferable to perform cholecystectomy within 24 h of endoscopic retrograde cholangiopancreatography to reduce conversion rate. Early laparoscopic cholecystectomy does not increase mortality, perioperative complications, or length of stay and on the contrary it reduces the risk of reoccurrence and progression of disease in the delay between endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy.

A newly synthesised molybdenum/ascorbic acid complex alleviates some effects of cardiomyopathy in streptozocin-induced diabetic rats.

BACKGROUND: Exogenous insulin does not prevent cardiac failure in patients with type 1 diabetes mellitus and a cardioprotective insulin mimic is greatly needed. Certain transition metals are known to act as insulin mimics and may be cardio- protective. In this study, the ability of a newly synthesised molybdenum/ascorbic acid complex to strengthen cardiac function was investigated. METHODS AND DESIGN: Male CD rats were assigned to one of five groups: non-diabetic control, non-diabetic control treated with molybdenum/ascorbic acid complex, diabetic treated with sodium ascorbate, diabetic treated with molybdenum/ascorbic acid complex and untreated diabetics. Type 1 diabetes was induced by streptozocin injection. Once diabetes was confirmed, treatment was initiated by adding either the molybdenum/ascorbic acid complex or sodium ascorbate to the drinking water and continued for 6 weeks. Following the treatment period, the animals were terminated, and their hearts were excised and mounted in a working heart perfusion apparatus. Blood samples were taken for plasma glucose and plasma lipid level determination. Cardiac function was evaluated using 1 hour of low-flow ischaemic stress followed by 30 minutes of reperfusion. RESULTS: Hearts from the animals treated with the molybdenum/ascorbic acid complex displayed the best aerobic performance of all the diabetic animals. Blood glucose levels and blood lipid levels were significantly lower in animals treated with the complex than in other diabetic animals. The group treated with the complex also had a lower drinking rate than the other diabetic groups. Furthermore, hearts from animals treated with the molybdenum/ascorbic acid complex showed a greater degree of recovery from low-flow ischaemia than any other group. CONCLUSIONS: The molybdenum/ascorbic acid complex showed some significant insulin-mimic and cardioprotective effects. Further development of this complex could provide a drug useful for alleviating some of the cardiovascular problems associated with diabetes mellitus.

Evaluation of a single dose versus a divided dose regimen of amoxycillin in treatment of Actinobacillus pleuropneumoniae infection in pigs.

The theory of a time-dependent effect of amoxycillin was examined in a model of porcine Actinobacillus pleuropneumoniae (Ap)-infection using clinically relevant dosage regimens. Twenty hours after infection of fourteen pigs, when clinical signs of pneumonia were present, one group of pigs received a single dose of amoxycillin (20 mg/kg, i.m.), whereas another group received four doses of 5 mg/kg injected at 8-h intervals. A similar AUC of the plasma amoxycillin concentration versus time curve was obtained in the two groups, whereas the maximum concentration was threefold higher using the single high dose. Plasma amoxycillin was above the MIC for twice as long using the fractionated dosage scheme. The condition of the animals was evaluated by clinical and haematological observations combined with quantification of biochemical infection markers: C-reactive protein, zinc and ascorbic acid. Within 48 h of treatment, the pigs in both treatment groups recovered clinically. No significant differences in the time-course of clinical observations or plasma concentrations of the biomarkers of infection were observed between the two treatments. In conclusion, the efficacy of these two dosage regimens of amoxycillin was not significantly different in treatment of acute Ap-infection in pigs.

Genome organisation and chromatin structure in Escherichia coli.

We have analysed the complete sequence of the Escherichia coli K12 isolate MG1655 genome for chromatin-associated protein binding sites, and compared the predicted location of predicted sites with experimental expression data from 'DNA chip' experiments. Of the dozen proteins associated with chromatin in E. coli, only three have been shown to have significant binding preferences: integration host factor (IHF) has the strongest binding site preference, and FIS sites show a weak consensus, and there is no clear consensus site for binding of the H-NS protein. Using hidden Markov models (HMMs), we predict the location of 608 IHF sites, scattered throughout the genome. A subset of the IHF sites associated with repeats tends to be clustered around the origin of replication. We estimate there could be roughly 6000 FIS sites in E. coli, and the sites tend to be localised in two regions flanking the replication termini. We also show that the regions upstream of genes regulated by H-NS are more curved and have a higher AT content than regions upstream of other genes. These regions in general would also be localised near the replication terminus.

Metabolism of sulfadiazine in neonatal and young pigs. Comparative in vivo and in vitro studies.

Metabolism of sulfadiazine (SDZ) was studied in vivo and in vitro during postnatal development of piglets in order to examine whether in vitro metabolism approaches the in vivo situation. Experiments were performed in 1-day-, 8-day- and 60-day-old piglets. In vivo: 14C-SDZ was injected intravenously and urine and tissue samples collected after 3 hr. Urinary excretion data as well as data from liver and kidney tissue indicated a relatively high capacity for acetylation at birth, while the capacity for oxidation is low during the first week of life. At 60 days of age the acetylation and oxidation of SDZ is equal each accounting for about 20% of the amount excreted in urine. In vitro: Incubation of subcellular fractions of liver and kidney showed that acetylation of SDZ in liver reached maximum within 1 week. Oxidative activity was absent at 1 day, present at a low level at day 8, and at a high level at day 60. Neither acetylation nor oxidation of SDZ took place in kidney. The results show a close correlation between in vivo and in vitro results with respect to the developmental pattern seen in piglets during the postnatal period of life.

The kinetic disposition of pyrantel citrate and pamoate and their efficacy against pyrantel-resistant Oesophagostomum dentatum in pigs.

The pharmacokinetic disposition of pyrantel after intravenous (i.v.) and oral (p.o.) administration as the citrate and p.o. administration as the pamoate salt was determined in pigs. Following i.v. administration pyrantel was quickly cleared from the bloodstream, exhibiting a terminal half-life of 1.75 +/- 0.19 h and a residence time (MRT) of 2.54 +/- 0.27 h. After p.o. administration as the citrate salt, the absorption time (MAT) of pyrantel was 2.38 +/- 0.25 h and although significant quantities of pyrantel were absorbed (mean bioavailability of 41%) the rapid clearance resulted in a MRT of only 4.92 +/- 0.36 h. By comparison, the significantly extended MAT of the less soluble pamoate salt resulted in reduced circulating concentrations and a significantly lower mean bioavailability of 16%. The poor efficacy of pyrantel citrate against nematodes inhabiting the large intestine of pigs is therefore suggested to result from insufficient quantities of drug passaging to the site of infection. When tested against pyrantel-resistant adult Oesophagostomum dentatum the mean efficacy of pyrantel citrate was only 23%, whereas the efficacy of the lesser absorbed pyrantel pamoate was 75%. These results indicate that for maximum activity pyrantel should be administered to pigs as the pamoate salt.

A new in vitro assay of benzimidazole activity against adult Oesophagostomum dentatum.

A new in vitro assay of benzimidazole activity against adult Oesophagostomum dentatum is described. The method is based on the ability of O. dentatum to migrate through polyamide nets after exposure to various concentrations of benzimidazole. To determine an appropriate mesh size, control worms and worms exposed to 10 microM oxfendazole for 24 h were allowed to migrate through nets with various mesh sizes (300-500 microns) for up to 1 h. A mesh size of 350 microns and migration periods of 10, 20 and 30 min were selected. Exposure to oxfendazole at 10 microM for 24, 48 and 72 h inhibited the migration in a time-dependent manner. After 72 h of exposure and with a 20-min migration period, the EC50 of oxfendazole for O. dentatum was 0.564 microM. In further studies the activities of albendazole sulphoxide, albendazole, cambendazole, fenbendazole, flubendazole, luxabendazole, mebendazole, oxfendazole, oxibendazole, parbendazole and thiabendazole were compared. The worms were exposed to each drug at two concentrations (0.1 and 3.16 microM) for 72 h. At 3.16 microM there were no significant differences in the activity of the drugs. At 0.1 microM significant differences in activity were found. Albendazole sulphoxide and oxfendazole were poor inhibitors of migration compared with their parent compounds, albendazole and fenbendazole.

Three views of microbial genomes.

We describe here GenomeAtlases as a method for visualising three different aspects of complete microbial chromosomes: repeats, DNA structural characteristics, and base composition. We have applied this method to all publicly available genomes, and find a general strand preference of global repeats. The atlas for the Mycoplasma genitalium genome is presented as an example, and results from all three views are consistent with known characteristics of the genome.

Uptake of ochratoxin A by slices of pig kidney cortex.

Ochratoxin A (OCT A) is a nephrotoxin causing selective necrosis of the proximal tubule. Being an organic anion OCT A might be expected to enter the tubule cells by the organic anion transport system. Pig renal cortical slices were used to characterize the OCT A transport. OCT A (5 X 10(-3) mM) was accumulated against a concentration gradient with a slice to medium ratio of 8.9 +/- 2.9 in the presence of oxygen. This accumulation was markedly reduced in a nitrogen atmosphere (S/M ratio = 2.9 +/- 0.5). OCT A accumulation was dependent on medium concentration. With increasing concentration (5 X 10(-4)-5 X 10(-1) mM), slice to medium ratio initially rose from 6.9 +/- 2.0 to 11.7 +/- 1.2 whereupon it declined to 5.4 +/- 1.1. This pattern indicates that both carrier mediated transport and intracellular metabolism may contribute to the net accumulation of the toxin. OCT A (10(-4) to 1 mM) inhibited p-aminohippurate (PAH) and phenolsulphophthalein (PSP) uptake in a dose-dependent manner. Up to 10(-1) mM, OCT A did not inhibit acetylation of PAH suggesting that aerobic metabolism and the energy supply for the transport process were unaffected. Kinetic studies revealed a competitive inhibition of the PSP transport. It is concluded that OCT A enters the proximal tubule cells by the common organic anion transport system.

The cytotoxic effect of paraquat to isolated renal proximal tubular segments from rabbits.

Paraquat (PQ) induces lung, liver and kidney damage. Since PQ mainly is eliminated by the kidney, the kidney damage is of particular importance to the outcome of PQ poisoning. The exact toxic mechanism of PQ is still unclear but it is assumed to involve redox cycling and formation of reactive oxygen species. In this study, further investigations on the toxic mechanism and metabolic effects of PQ were performed using isolated renal proximal tubules from rabbits. Proximal tubules were isolated using a combined iron perfusion and collagenase method. Suspended tubules were incubated for varying periods and concentrations of PQ at 25 or 37 degrees C in Krebs-Ringer phosphate buffer or HCO3-/CO2 buffer. The cytotoxic effect of PQ was evaluated by (1) markers of oxidative stress: status of glutathione (GSH/GSSG) and formation of malondialdehyde (MDA); and (2) markers of tubular metabolism: oxygen consumption (QO2), transport of 14C-p-aminohippuric acid (PAH) and 14C-tetraethylammonium (TEA). Using 0.5 and 5 mM PQ, the GSH/GSSG ratio decreased whereas formation of MDA increased indicating oxidative stress. PQ reduced the accumulation of PAH and TEA, the basal QO2 and the ouabain sensitive QO2 indicating inhibition of the Na/K-ATPase. Nystatin-stimulated QO2 was reduced by PQ, excluding inhibition of Na+ entry as a possible cytotoxic mechanism and suggesting mitochondrial injury. This was confirmed by measuring FCCP-uncoupled QO2. Thus high concentrations of PQ appear to disrupt mitochondrial electron chain transfer resulting in reduction of metabolic functions.

Pig hepatocytes as an in vitro model to study the regulation of human CYP3A4: prediction of drug-drug interactions with 17 alpha-ethynylestradiol.

The objective of this study was to provide evidence of the validity of pig hepatocytes as a model to study the regulation of human CYP3A4 with special emphasis on drug-drug interactions. Thirteen different drugs were incubated with primary monolayer cultures of pig hepatocytes (n = 4). The study included both drugs reported to cause drug interactions in the clinic with 17 alpha-ethynylestradiol (EE2), other drugs metabolized by CYP3A4, and drugs not reported to cause any problems. Effect of the drug exposure to pig hepatocytes was determined by immunodetection using a monoclonal human CYP3A4 antibody and measurement of 6 beta-hydroxylation of testosterone and 2-hydroxylation of 17 alpha-ethynylestradiol (EE2), both reactions known to be catalyzed by CYP3A4 in humans. Data were compared to data from human hepatocytes and to reported observations of drug-drug interactions in the clinic. The drugs known to be inducers of CYP3A4 in humans significantly increased a CYP isoform in pigs catalyzing 6 beta-hydroxylation of testosterone and 2-hydroxylation of EE2, whereas drugs not reported to have clinical interactions with EE2 had no or only marginal effect. Induction by the drugs known to be inducers of CYP3A4 increased with drug exposure time and the CYP3A4 activity, represented by testosterone 6 beta-hydroxylation, was highest at 72 h for the investigated induction periods (24, 48 and 72 h), except for dexamethasone where the effect peaked after 24 h. Induction of the 2-hydroxylation of EE2 correlated well with the increase in 6 beta-hydroxylation of testosterone (except for sulphinpyranzone) and the increase in the protein level of CYP3A detected by a monoclonal human CYP3A4 antibody, thus confirming the 2-hydroxylation of EE2 in pigs as being biotransformed by a CYP isoform presumably belonging to the CYP3A subfamily as in humans. In conclusion, these results indicate that pig hepatocytes may be a valuable model to mimic the regulation of human CYP3A4.

Glucose uptake in Oesophagostomum dentatum and the effect of oxfendazole.

The uptake of 14C-glucose by adult Oesophagostomum dentatum was characterised. The uptake was a non-linear function of external glucose concentration. The maximum velocity of uptake (Vmax) was 0.964 nmol/100 mg dry weight (dw)/5 min, and the transport constant (Kt) was 10.02 microM. When phlorizin, phloretin and 3-O-methylglucose were tested for their effects on the uptake of 14C-glucose, phloretin and 3-O-methylglucose produced significant inhibitions, indicating that the uptake was mediated and occurred by facilitated diffusion. Exposure of the worms to oxfendazole prior to incubation with 14C-glucose did not affect the uptake of glucose. In another experiment worms were incubated with unlabelled glucose and the external glucose concentration was measured enzymatically. During a 7 h incubation period, the quantity of glucose remaining in the incubation medium of oxfendazole exposed worms was significantly greater than in the control group. It was concluded that oxfendazole did not influence the process of 14C-glucose uptake, but might induce changes in the parasite leading to a reduced ability to deplete the incubation medium of glucose.

Penetration of amoxycillin into the respiratory tract tissues and secretions in pigs.

The pharmacokinetic properties of amoxycillin, and its penetration into respiratory tract tissues (alveolar macrophages, bronchial secretions, bronchial mucosa, lung tissue and lymph nodes), were determined in 20 healthy female pigs weighing 29 to 55 kg, after a single intravenous dose of 8.6 mg kg(-1) bodyweight. Following intravenous administration the plasma concentration-time curves were best described by a three-compartment open model. The elimination half-life and the mean residence time were 2.5 and 1.4 hours, respectively. The volume of distribution at steady state was 0.52 litres kg(-1), and the body clearance was 0.40 litres hour(-1) kg(-1). In all structures (except alveolar macrophages) amoxycillin concentration peaked at the first sampling point, one hour after drug administration. The tissue to plasma ratio (based on AUC values) were 0.33 for bronchial secretions, 0.37 for bronchial mucosa, 0.39 for lung tissue and 0.68 for lymph nodes. Traces of amoxycillin were found in alveolar macrophages, but the concentrations were below the limit of quantification. The concentration of amoxycillin in secretions and tissue decreased by a slower rate than the concentration in plasma, resulting in increasing secretion- and tissue-to-plasma concentration ratios.

Pharmacokinetics and penetration of danofloxacin into the gastrointestinal tract in healthy and in Salmonella typhimurium infected pigs.

The pharmacokinetics and penetration of danofloxacin into the gastrointestinal tract in healthy pigs and in pigs experimentally infected with Salmonella typhimurium were studied. In the infected pigs, a decrease in body clearance and an increase in mean elimination half-life was observed (P < 0.01). Moreover a significant reduction in the volume of the peripheral compartment was found. Danofloxacin distributed well to the gastrointestinal tract achieving high AUC / AUC(plasma)ratios in both groups of pigs. However, compared to the healthy pigs AUC / AUC(plasma)ratios decreased in the infected pigs. Salmonella infection led to an increase in mean residence time (MRT) in the small intestines and lymph nodes and a decrease in MRT in caecum and colon.