A systematic review of outcomes in postoperative pain studies in paediatric and adolescent patients: towards development of a core outcome set.

Systematic reviews of postoperative pain in children have called into question the consistency of outcomes measured by clinical triallists as well as the measurement instruments used for assessment. Core outcome set methodology may be a solution to improve standardisation. This study provides an evidence-based foundation for the development of a core outcome set for paediatric postoperative pain studies. We searched ClinicalTrials.gov to identify relevant postoperative pain studies in children. The search yielded 300 registered trials. The following data were then extracted from each of the trials: phase of trial; study type; study design; sample size; all outcomes; whether the outcome was listed as primary, secondary, or tertiary; the measurement instrument for each reported outcome; the specific metric for each outcome; and the type of clinical procedure. Following screening, 134 studies were included in our study. Pain measurement was the most commonly reported outcome (n = 123), followed by total postoperative analgesic dosage (n = 83) and side-effects (n = 25). Temporal trends indicated that pain assessment and unexpected events increased in use between 2000 and 2016, whereas postoperative analgesia measurement decreased. We found a lack of standardisation among outcomes and measurement instruments in paediatric postoperative pain studies. Development of a core outcome set may improve the quality of future trials and allow for more accurate study-to-study comparisons.

Home medicines reviews in Australian war veterans taking warfarin do not influence international normalised ratio control.

BACKGROUND: The clinical outcomes of warfarin are largely dependent on the international normalised ratio (INR) control achieved, and strategies to improve the time in therapeutic range (TTR) should be identified and widely implemented in practice. AIMS: To investigate the influence of pharmacist-led medication reviews on INR control and observe the quality of INR control in Australian veterans who take warfarin. METHODS: We undertook a retrospective cohort study using administrative claims data for Australian veterans and war-widows identified by the Department of Veterans' Affairs who were regularly dispensed warfarin and invited them to contact the research team. Pathology providers were subsequently contacted to provide INR results. RESULTS: INR data were available for 344 of 818 (42.1%) veterans who consented to participate in the study; 64.4% were male and the median age was 83 years. The overall TTR for the veteran cohort during the study period was 64.0%. There was no difference in the TTR in the 6 months following home medicines review (HMR) compared with the control group (63.0% vs 67.0%, P = 0.27), with the TTR in patients with INR data available in the 6 months prior to, and the 6 months following HMR, remaining high (67.9% vs 69.6% P = 0.63). Approximately, one-third of veterans in this study had a percentage TTR below 60%. CONCLUSIONS: INR was well-controlled in this elderly cohort, comparable to that achieved in recent randomised trials involving warfarin. Pharmacist-led medication reviews were not associated with a change in INR control.

Perinatal Treponema pallidum: evidence based guidelines to reduce mother to child transmission.

Universal antenatal screening for T. pallidum is standard in Irish maternity units. The prevalence of adult syphilis has increased in Ireland. We audited the neonatal management of infants exposed to T. pallidum in utero. A cross sectional retrospective analysis of all pregnancies with confirmed positive serology for T. pallidum from January 2005 to December 2010 was conducted at the National Maternity Hospital, Holles St. Data were analysed using SPSS 14.0. Ethical approval was obtained. There were 55,058 live births during the study period. Fifty-eight women had positive serology and 41 met inclusion criteria. Infant evaluation and follow up was decided by allocation to an evidence based algorithm. Twenty-one infants (51%) were accurately allocated and assessed, 5 (12%) had a partial assessment and the algorithm was incorrectly applied in 15 (36%) of cases. Failure to adhere to evidence based neonatal guidelines is common and undermines efficacy of the screening program.

The potential for intelligent decision support systems to improve the quality and consistency of medication reviews.

WHAT IS KNOWN AND OBJECTIVE: Drug-related problems (DRPs) are of serious concern worldwide, particularly for the elderly who often take many medications simultaneously. Medication reviews have been demonstrated to improve medication usage, leading to reductions in DRPs and potential savings in healthcare costs. However, medication reviews are not always of a consistently high standard, and there is often room for improvement in the quality of their findings. Our aim was to produce computerized intelligent decision support software that can improve the consistency and quality of medication review reports, by helping to ensure that DRPs relevant to a patient are overlooked less frequently. A system that largely achieved this goal was previously published, but refinements have been made. This paper examines the results of both the earlier and newer systems. METHODS: Two prototype multiple-classification ripple-down rules medication review systems were built, the second being a refinement of the first. Each of the systems was trained incrementally using a human medication review expert. The resultant knowledge bases were analysed and compared, showing factors such as accuracy, time taken to train, and potential errors avoided. RESULTS AND DISCUSSION: The two systems performed well, achieving accuracies of approximately 80% and 90%, after being trained on only a small number of cases (126 and 244 cases, respectively). Through analysis of the available data, it was estimated that without the system intervening, the expert training the first prototype would have missed approximately 36% of potentially relevant DRPs, and the second 43%. However, the system appeared to prevent the majority of these potential expert errors by correctly identifying the DRPs for them, leaving only an estimated 8% error rate for the first expert and 4% for the second. WHAT IS NEW AND CONCLUSION: These intelligent decision support systems have shown a clear potential to substantially improve the quality and consistency of medication reviews, which should in turn translate into improved medication usage if they were implemented into routine use.

A methodological framework for estimating the clinical and economic value of community pharmacists' clinical interventions using expert opinion.

WHAT IS KNOWN AND OBJECTIVE: Studies of the outcomes of clinical interventions (CIs) performed by community pharmacists are limited. The economic models used in most studies of CIs have been simplistic, often failing to fully capture the counterfactual when estimating savings in health resources resulting from CIs. This paper aimed to describe the complexities involved in estimating the clinical and economic outcomes of CIs performed by community pharmacists when using expert opinion and suggest avenues for improvement. METHODS: Existing models were reviewed, from which a range of key parameters required to evaluate the outcomes of CIs were identified. The considerations necessary to generate potentially more robust estimates of these parameters were discussed. RESULTS AND DISCUSSION: CIs performed by community pharmacists may result in a multitude of effects on numerous health services. By utilizing the approaches described in this paper, researchers working in this field should be able to generate improved estimates of health resource savings and quality of life effects resulting from CIs performed by community pharmacists, when compared to previous efforts. WHAT IS NEW AND CONCLUSION: This article offers recommendations designed to improve the robustness of evaluation when using expert opinion to evaluate CIs performed by community pharmacists.

Inappropriate prescribing in older residents of Australian care homes.

WHAT IS KNOWN AND OBJECTIVE: The incidence of inappropriate prescribing is higher amongst the older age group than the younger population. Inappropriate prescribing potentially leads to drug-related problems such as adverse drug reactions. We aimed to determine the prevalence of inappropriate prescribing in residents of Tasmanian (Australia) residential care homes using Beers and McLeod criteria. METHODS: Patient demographics, medical conditions and medications were collected from medical records. The patients who fulfilled either Beers or McLeod criteria were identified and the characteristics of these patients were then compared. RESULTS: Data for 2345 residents were collected between 2006 and 2007. There were 1027 (43.8%) patients prescribed at least one inappropriate medication. Beers criteria identified more patients (828 patients, 35.3%) as being prescribed inappropriate medication compared with McLeod criteria (438 patients, 18.7%). Patients taking psychotropic medication/s, more than six medications or diagnosed with five or more medical conditions were more likely to be prescribed an inappropriate medication (P<0.001). The most frequently identified inappropriate medications included benzodiazepines, amitriptyline, oxybutynin and non-steroidal anti-inflammatory drugs. WHAT IS NEW AND CONCLUSION: Inappropriate prescribing, as defined by either Beers criteria or McLeod criteria, is relatively common in Australian nursing homes. The prevalence of inappropriate prescribing, and factors influencing it, are consistent with other countries. Both Beers and McLeod criteria are a general guide to prescribing, and do not substitute for professional judgment.

Laparoscopic adrenalectomy: Single centre experience.

BACKGROUND: Laparoscopic adrenalectomy is an attractive alternative to the traditional open approach in the surgical excision of an adrenal gland. It has replaced open adrenalectomy in our institution and we review our experience to date. METHODS: All cases of laparoscopic adrenalectomies in our hospital over eight years (from 2001 to May 2009) were retrospectively reviewed. Patient demographics, diagnosis, length of hospital stay, histology and all operative and post-operative details were evaluated. RESULTS: Fifty-five laparoscopic adrenalectomies (LA) were performed on 51 patients over eight years. The mean age was 48 years (Range 16-86 years) with the male: female ratio 1:2. Twenty-three cases had a right adrenalectomy, 24 had a left adrenalectomy and the remaining four patients had bilateral adrenalectomies. 91% were successfully completed laparoscopically with five converted to an open approach. Adenomas (functional and non functional) were the leading indication for LA, followed by phaeochromocytomas. Other indications for LA included Cushing's disease, adrenal malignancies and rarer pathologies. There was one mortality from necrotising pancreatitis following a left adrenalectomy for severe Cushing's disease, with subsequent death 10 days later. CONCLUSION: Laparoscopic adrenalectomy is effective for the treatment of adrenal tumours, fulfilling the criteria for the ideal minimally invasive procedure. It has replaced the traditional open approach in our centre and is a safe and effective alternative. However, in the case of severe Cushing's disease, laparoscopic adrenalectomy has the potential for significant adverse outcomes and mortality.

Aberrant right posterior sectoral duct injury necessitating liver resection.

Aberrant insertion of the right posterior sectoral duct is a particularly hazardous variation of biliary anatomy which makes it prone to injury during laparoscopic cholecystectomy. Such injuries are challenging to manage, as multiple therapeutic options are available with no clear consensus in the literature for an optimal approach. Options include conservative management, intraoperative ligation of the injured duct, Roux-en-Y reconstruction and segmental liver resection. Most cases in the literature advocate for nonoperative management or hepaticojejunostomy. We present an unusual case of aberrant right posterior sectoral duct injury in which neither of these approaches was viable, necessitating a bi-segmental liver resection.

Non-genetic factors that influence methamphetamine intake in a genetic model of differential methamphetamine consumption.

RATIONALE: Genetic and non-genetic factors influence substance use disorders. Our previous work in genetic mouse models focused on genetic factors that influence methamphetamine (MA) intake. The current research examined several non-genetic factors for their potential influence on this trait. OBJECTIVES: We examined the impact on MA intake of several non-genetic factors, including MA access schedule, prior forced MA exposure, concomitant ethanol (EtOH) access, and gamma-aminobutyric acid type B (GABAB) receptor activation. Selectively bred MA high drinking (MAHDR) and low drinking (MALDR) mice participated in this research. RESULTS: MAHDR, but not MALDR, mice increased MA intake when given intermittent access, compared with continuous access, with a water choice under both schedules. MA intake was not altered by previous exposure to forced MA consumption. Male MAHDR mice given simultaneous access to MA, EtOH, and an EtOH+MA mixture exhibited a strong preference for MA over EtOH and EtOH+MA; MA intake was not affected by EtOH in female MAHDR mice. When independent MAHDR groups were given access to MA, EtOH, or EtOH+MA vs. water in each case, MA intake was reduced in the water vs. EtOH+MA group, compared with the water vs. MA group. The GABAB receptor agonist R(+)-baclofen (BAC) not only reduced MA intake but also reduced water intake and locomotor activity in MAHDR mice. There was a residual effect of BAC, such that MA intake was increased after termination of BAC treatment. CONCLUSIONS: These findings demonstrate that voluntary MA intake in MAHDR mice is influenced by non-genetic factors related to MA access schedule and co-morbid EtOH exposure.

Primary colorectal linitis plastica presenting as rapid acute deterioration: a diagnostic dilemma.

We present a rare case of primary colorectal linitis plastica presenting as an acute admission to hospital with a wide range of systemic symptoms, sudden rapid deterioration and subsequent mortality. A postmortem examination revealed a primary linitis plastica of the colon and rectum with diffuse metastatic disease. To our knowledge, this is the first report of primary colorectal linitis plastica presenting as an acute deterioration as a result of extensive metastatic disease.

Quantitative magnetic resonance angiography of the cerebrovasculature in physiologic and pathologic states.

BACKGROUND: In the past, clinical decisions regarding treatment of neurovascular disorders leading to ischemia have been guided by the percentage of stenosis of the vessel in question. However, such an approach assumes a predictable and stable relationship between the percentage of stenosis and the degree of flow reduction it causes. Historically, this type of relationship has been difficult to document. Thus, a method for noninvasively measuring the absolute flow of specific cerebral arteries is of potential practical value. METHODS: We set to quantify the mean blood flow (Qm, in mL/min) in the cerebral arteries using quantitative magnetic resonance angiography (QMRA), and to compare the findings in normal vessels with those found in vessels considered pathologically narrowed. Specific vascular segments were identified, studied, and the results entered into a database. Statistical analyses of the measurements were carried out using StatPlus for Microsoft Excel. It involved comparing of the Qm found in specific vessels, as well as those found in normal and abnormal vessels, using analysis of variance (ANOVA). The abnormal vessels were selected from specifically identified magnetic resonance angiography (MRA) studies. RESULTS: A total of 57 patients, 26 men and 31 women, with ages ranging from 19 to 86 years (mean = 64.5), underwent MRA with subsequent QMRA of 157 arteries. The latter included 72 internal carotid (ICA), 45 vertebral (VA), 18 common carotid (CCA), 13 middle cerebral (MCA), and nine basilar (BA) arteries. The mean Qm obtained were CCA = 313.9 (+/-115.4), ICA = 231.1 (+/-83.7), VA = 90.5 (+/-45.8), MCA = 92.5 (+/-62.3) and BA = 120.1 (+/-64.5). ANOVA showed significant differences between individual vessels (P < .00001). The values obtained were consistent with those predicted mathematically, as derivatives of their proportional contributions to overall cerebral arterial flow (Qbrain) as a product of the normal cardiac output (CO) [ie, Qbrain = CO*.2]. Further ANOVA of the normal and abnormal vessels showed statistically significant differences between the two groups (186.5 +/- 108.6 vs. 117.9 +/- 76.1, respectively; P= .000514). CONCLUSIONS: The use of QMRA provides the mean for direct measurement of absolute blood flow within the cerebral arteries in physiologic and pathologic states. This technique may be of future importance in characterizing absolute flow compromise in the cerebral arteries under a variety of clinically relevant circumstances.

Increased accumulation of drugs in a multidrug resistant cell line by alteration of membrane biophysical properties.

Growth of CHRC5 multidrug resistant cells in media enriched in a saturated C-17 fatty acid, heptadecanoic acid, resulted in these cells accumulating vinblastine at a rate and to an extent comparable to that of the parental cell line AB1. The fatty acid-enriched growth media had no effect on the ability of AB1 cells to take up vinblastine. The action of amphiphiles on the uptake of rhodamine dyes by CHRC5 cells was compared with the increased dye accumulation affected by verapamil. Membrane rigidifying agents, such as the saturated fatty acid stearic acid, or the cholesterol derivatives, cholesteryl hemisuccinate and cholesteryl phosphorylcholine, as well as a membrane fluidizing unsaturated fatty acid, linoleic acid, could significantly increase dye uptake, although not as well as verapamil. These results taken in conjunction with other reports in the literature, demonstrate that multidrug resistance is sensitive to alterations of membrane properties. They suggest that perturbation of the membrane to either increased or to decreased membrane fluidity can lower the level of resistance.

Dimerization of the P-glycoprotein in membranes.

Plasma membranes from a CHO cell line, CHRC5, which exhibits multidrug resistance was studied using radiation inactivation analysis. The P-glycoprotein content of the membrane was determined by Western blots. Irradiation resulted in the loss of P-glycoprotein. The dependence of this loss on radiation dose corresponded to a target size of 250 kDa which is the molecular mass of a dimer of the P-glycoprotein. This is strong evidence to indicate that the P-glycoprotein self associates in the membrane.

Calcitonin inhibits the rise of intracellular calcium induced by thyrotropin-releasing hormone in GH3 cells.

Both human and salmon calcitonins markedly inhibit the TRH-stimulated rise in intracellular [Ca2+] in GH3 cells. Calcitonin also inhibits prolactin release from these cells. Both [Ala] salmon calcitonin and salmon calcitonin (1-23) peptide amide also inhibit this rise in [Ca2+] and also inhibit TRH-stimulated prolactin release from GH3 cells as well as from primary pituitary cell cultures. It is likely that calcitonin inhibits prolactin release in the pituitary by decreasing the extent of the rise of intracellular calcium concentration. Neither an intact disulfide bond at the amino terminus nor residues 24-32 of the carboxyl terminus of salmon calcitonin are required for this inhibition.

Zwitterionic amphiphiles that raise the bilayer to hexagonal phase transition temperature inhibit protein kinase C. The exception that proves the rule.

We synthesized the zwitterionic amphiphile cholesterylphosphorylethylpyridinium. This substance activated protein kinase C (PKC) in a micelle-based assay, but in a vesicle assay it was inhibitory. An analog of this compound, in which the pyridine ring is saturated and the nitrogen methylated, showed similar behaviour with PKC. Replacing cholesterol by an aliphatic alcohol lowered the extent of activation in the micelle assay. These results demonstrate that, with some membrane additives, the vesicle and micelle assays give opposite results. Results from the membrane-based vesicle assay for PKC are in accord with the generalization that zwitterionic amphiphiles that raise the bilayer to hexagonal phase transition temperature in model membranes are inhibitors of PKC.

The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model.

Although hirudin is better than heparin at preventing recurrent ischemia in patients with unstable angina, hirudin produces more bleeding. The purpose of this study was to use a rabbit arterial thrombosis prevention and ear bleeding model to determine whether for equivalent efficacy, melagatran, a synthetic direct thrombin inhibitor, is safer than hirudin. A combination of balloon injury and stasis was used to induce thrombosis in the distal aorta, and patency and blood flow were continuously monitored with ultrasonic flow probes. Rabbits were randomized to melagatran (in total doses of 78-313 nmol kg(-1)), hirudin (in total doses of 18-107 nmol kg(-1)), or saline over 90 min. To assess safety, blood loss from standardized ear incisions was measured. Both melagatran and hirudin produced dose-dependent increases in patency and blood flow. At doses that maintained the highest levels of patency, however, melagatran produced 2-3-fold less bleeding than hirudin. Thus, at maximally effective doses, melagatran causes less bleeding than hirudin in this model. These findings raise the possibility that some direct thrombin inhibitors are safer than others.

Deletion sequences of salmon calcitonin that retain the essential biological and conformational features of the intact molecule.

Salmon calcitonin has an amino acid sequences that would allow it to form an amphipathic helix from approximately residue 9 to residue 22. We have synthesized a number of analogues of this peptide hormone with deletions in the carboxyl terminus of this putative amphipathic helix. These analogues include deletions of single amino acid residues at positions 19, 20, 21, or 22 as well as deletions of progressively larger segments starting with residue 19 and including deletions of residues 19 and 20; 19, 20, and 21; or 19, 20, 21, and 22. There is a small decrease in the helical content of these analogues compared with the native hormone, both in the presence and absence of amphiphiles. However, the extent of formation of secondary structure, as measured by circular dichroism, is similar for these deletion sequences as it is for the native hormone. In all cases, there is a large increase in the helical content of the peptide in the presence of dimyristoylphosphatidylglycerol, lysolecithin, or sodium dodecyl sulfate. All of the analogues have hypocalcemic activity in vivo in rats, comparable to the native hormone, except for des-Leu19-salmon calcitonin, which is about twice as active as the unmodified hormone. With use of an in vitro assay of adenylate cyclase activation in purified rat kidney membranes, des-Tyr22-salmon calcitonin, des-Leu19,Gln20,Thr21-salmon calcitonin, and des-Leu19Gln20,Thr21,Thr22-salmon calcitonin exhibited about one-tenth the stimulatory activity of the native hormone. Des-Tyr22-sCT and des-Leu19,Gln20,Thr21,Tyr22-sCT were also tested for their activity in inhibiting prolactin release from isolated rat pituitary cells. Both of these analogues exhibited inhibitory activity. Thus, the region of residues 19-22 does not greatly affect either the conformational or the biological properties of salmon calcitonin.

Serial echocardiographic appearance of healing bacterial vegetations.

Serial M mode and cross-sectional echocardiograms were obtained from six patients who had been treated with antibiotic drugs for infectious endocarditis. Three to six M mode echocardiograms and one to six cross-sectional echocardiograms were obtained from each patient over a follow-up period averaging 50 weeks (range 10 to 108 weeks). On echocardiography, vegetations were observed to have become smaller and more echo-reflective with healing. A dramatic change was seen in two patients after peripheral embolization. M mode echocardiography was particularly helpful in determining the quality of echo reflection by vegetations; cross-sectional echocardiography was more helpful in judging the size and shape of a vegetation. Echocardiography is ideally suited for the serial visualization of healing vegetations in patients who do not require early valve replacement. It may prove helpful to examine serially valve vegetations with both M mode and cross-sectional echocardiography when following up patients with infectious endocarditis treated with antibiotic agents.

Actions of adrenaline on the potassium balance of the isolated heart.

1. The action of adrenaline on the K(+) balance of the isolated heart was found to depend on the ionic composition and the temperature of the perfusion fluids used.2. When the perfusion fluid contained 145 mM Na(+), 1.7 mM Ca(++) and 3-9 mM K(+), adrenaline caused the hearts to gain K(+); when the K(+) concentration was reduced to 1.2 mM, adrenaline caused a loss of K(+). Both were actions on beta receptors.3. When the Ca(++) or the Na(+) concentration in the perfusion fluid was reduced, together with a reduction in K(+), adrenaline no longer produced K(+) loss from the hearts, but produced a gain of K(+).4. When the temperature of the perfusion fluid was reduced to 25 degrees C, adrenaline still produced a gain of K(+) by hearts perfused with fluid containing 3.2 mM K(+), but did not produce a loss of K(+) from hearts perfused with fluid containing 1.2 mM K(+).