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"Chapman, Peter"
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Is colchicine prophylaxis required with start-low go-slow allopurinol dose escalation in gout? A non-inferiority randomised double-blind placebo-controlled trial
ObjectivesTo determine whether placebo is non-inferior to low-dose colchicine for reducing gout flares during the first 6 months of allopurinol using the ‘start-low go-slow’ dose approach.MethodsA 12-month double-blind, placebo-controlled non-inferiority trial was undertaken. Adults with at least one gout flare in the preceding 6 months, fulfilling the American College of Rheumatology (ACR) recommendations for starting urate-lowering therapy and serum urate ≥0.36 mmol/L were recruited. Participants were randomised 1:1 to colchicine 0.5 mg daily or placebo for the first 6 months. All participants commenced allopurinol, increasing monthly to achieve target urate <0.36 mmol/L. The primary efficacy outcome was the mean number of gout flares/month between 0 and 6 months, with a prespecified non-inferiority margin of 0.12 gout flares/month. The primary safety outcome was adverse events over the first 6 months.ResultsTwo hundred participants were randomised. The mean (95% CI) number of gout flares/month between baseline and month 6 was 0.61 (0.47 to 0.74) in the placebo group compared with 0.35 (0.22 to 0.49) in the colchicine group, mean difference 0.25 (0.07 to 0.44), non-inferiority p=0.92. There was no difference in the mean number of gout flares/month between randomised groups over the 12-month period (p=0.68). There were 11 serious adverse events in 7 participants receiving colchicine and 3 in 2 receiving placebo.ConclusionsPlacebo is not non-inferior to colchicine in prevention of gout flares in the first 6 months of starting allopurinol using the ‘start-low go-slow’ strategy. After stopping colchicine, gout flares rise with no difference in the mean number of gout flares/month between groups over a 12-month period.Trial registration numberACTRN 12618001179224.
Journal Article
Prefrontal Cortex Activation and Young Driver Behaviour: A fNIRS Study
Road traffic accidents consistently show a significant over-representation for young, novice and particularly male drivers. This research examines the prefrontal cortex activation of young drivers and the changes in activation associated with manipulations of mental workload and inhibitory control. It also considers the explanation that a lack of prefrontal cortex maturation is a contributing factor to the higher accident risk in this young driver population. The prefrontal cortex is associated with a number of factors including mental workload and inhibitory control, both of which are also related to road traffic accidents. This experiment used functional near infrared spectroscopy to measure prefrontal cortex activity during five simulated driving tasks: one following task and four overtaking tasks at varying traffic densities which aimed to dissociate workload and inhibitory control. Age, experience and gender were controlled for throughout the experiment. The results showed that younger drivers had reduced prefrontal cortex activity compared to older drivers. When both mental workload and inhibitory control increased prefrontal cortex activity also increased, however when inhibitory control alone increased there were no changes in activity. Along with an increase in activity during overtaking manoeuvres, these results suggest that prefrontal cortex activation is more indicative of workload in the current task. There were no differences in the number of overtakes completed by younger and older drivers but males overtook significantly more than females. We conclude that prefrontal cortex activity is associated with the mental workload required for overtaking. We additionally suggest that the reduced activation in younger drivers may be related to a lack of prefrontal maturation which could contribute to the increased crash risk seen in this population.
Journal Article
Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study
ObjectivesTo determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout.MethodsPeople, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24.ResultsThe mean (SE) change in SU from month 12 to 24 was −1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups.ConclusionsThe majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment.Trial registration numberACTRN12611000845932
Journal Article
A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout
ObjectivesTo determine the efficacy and safety of allopurinol dose escalation using a treat-to-target serum urate (SU) approach.MethodsA randomised, controlled, parallel-group, comparative clinical trial was undertaken. People with gout receiving at least creatinine clearance (CrCL)-based allopurinol dose for ≥1 month and SU ≥6 mg/dL were recruited. Participants were randomised to continue current dose (control) or allopurinol dose escalation for 12 months. In the dose escalation group, allopurinol was increased monthly until SU was <6 mg/dL. The primary endpoints were reduction in SU and adverse events (AEs).Results183 participants (93 control, 90 dose escalation) were recruited. At baseline, mean (SD) urate was 7.15 (1.6) mg/dL and allopurinol dose 269 mg/day. 52% had CrCL<60 mL/min. Mean changes in SU at the final visit were −0.34 mg/dL in the control group and −1.5 mg/dL in the dose escalation group (p<0.001) with a mean difference of 1.2 mg/dL (95% CI 0.67 to 1.5, p<0.001). At month 12, 32% of controls and 69% in the dose escalation had SU <6 mg/dL. There were 43 serious AEs in 25 controls and 35 events in 22 dose escalation participants. Only one was considered probably related to allopurinol. Five control and five dose escalation participants died; none was considered allopurinol related. Mild elevations in LFTs were common in both groups, a few moderate increases in gamma glutamyl transferase (GGT) were noted. There was no difference in renal function changes between randomised groups.ConclusionsHigher than CrCL-based doses of allopurinol can effectively lower SU to treatment target in most people with gout. Allopurinol dose escalation is well tolerated.Trial registration number: ANZCTR12611000845932; Results.
Journal Article
Total Suspended Solids Effects on Freshwater Lake Biota Other than Fish
Protective benchmarks for the effects of total suspended solids (TSS) on freshwater aquatic biota primarily focus on fish; whether these benchmarks will also protect their prey or co-existing lower trophic level aquatic biota was uncertain. We conducted an extensive literature review of TSS effects on those organisms comprising the food webs upon which fish living in lakes depend: phytoplankton, zooplankton, periphyton, and benthic invertebrates. The available literature indicates that TSS benchmarks that protect sensitive life stages of lake fish will also protect their supporting food webs; in other words, the function of lake aquatic communities will be protected and maintained.
Journal Article
Environmental quality benchmarks—the good, the bad, and the ugly
Environmental quality benchmarks (EQBs) such as water or sediment quality guidelines comprise one line of evidence for assessing the potential harm from chemicals and other stressors (physical, biological). They are useful but not perfect tools, should not always be used, and should never be used alone for final decision-making. The “good” can be designed to be situation-specific and can provide understandable scientific input to decision-makers. The “bad” includes perception that they are absolutes (i.e., definitive binary decision points), no or limited adaptability based on good science or common sense, and protection of individual organisms not populations of organisms. The “ugly” includes benchmarks based on simplistic indices (information loss, misleading results), misuse of biomarkers, and misapplication of EQBs. Other factors to be considered include the following: appropriately deriving EQBs, uncertainty, the laboratory is not the field, contaminant uptake and cause-effect, and specifics regarding sediment quality benchmarks (i.e., their specific “good,” “bad,” and “ugly” components). EQBs are not always needed or useful.
Journal Article
Adjusted calcium concentration as a predictor of ionized hypocalcemia in hypoalbuminemic dogs
Background Ionized calcium (iCa) is the biologically active fraction of total calcium (tCa) with clinical relevance to evaluate calcium homeostasis, but not all primary veterinarians have access to serum iCa. Formulas that adjust tCa to correct for variability in serum protein concentrations were not designed to predict iCa and are considered unreliable surrogates for iCa. Objectives To determine whether adjusted calcium concentration (aCa) can predict ionized hypocalcemia in hypoalbuminemic dogs without hyperphosphatemia. Animals A total of 262 hypoalbuminemic dogs without hyperphosphatemia. Methods Retrospective review of paired tCa and iCa. Patients were included if serum albumin concentration was ≤2.5 g/L and serum phosphorus concentration was ≤5 mg/dL. The aCa was calculated using tCa (mg/dL) − serum albumin concentration (g/dL) + 3.5 (g/dL). Sensitivity, specificity, positive (PPVs) and negative (NPVs) predictive values, and accuracy were determined for tCa and aCa at predicting any (<1.13 mmol/L) and moderate (<1.02 mmol/L) ionized hypocalcemia. Patients also were stratified into mild‐to‐moderate (2.0‐2.5 g/dL) and severe hypoalbuminemia (<2.0 g/dL). Results A total of 4296 dogs had paired results of which 262 met the inclusion criteria. Of these, 35 (13.4%) dogs had iCa < 1.13 mmol/L and 13 dogs (5.0%) had concentrations <1.02 mmol/L. The sensitivity, specificity, NPVs and PPVs of a decreased tCa and aCa for detecting moderate ionized hypocalcemia were 100% and 92.3%, 57.8% and 94.8%, 100% and 99.6%, and 11.0% and 48.2%, respectively, and accuracy was 60.0% and 94.7%, respectively. Conclusions A low aCa was useful to detect ionized hypocalcemia in hypoalbuminemic nonhyperphosphatemic dogs. A normal aCa indicated that moderate ionized hypocalcemia was unlikely.
Journal Article