Apparent stability masks underlying change in a mule deer herd with unmanaged chronic wasting disease.

The contagious prion disease "chronic wasting disease" (CWD) infects mule deer (Odocoileus hemionus) and related species. Unchecked epidemics raise ecological, socioeconomic, and public health concerns. Prion infection shortens a deer's lifespan, and when prevalence (proportion of adults infected) becomes sufficiently high CWD can affect herd dynamics. Understanding population responses over time is key to forecasting long-term impacts. Here we describe unexpected stability in prevalence and abundance in a mule deer herd where CWD has been left unmanaged. High apparent prevalence (~30%) since at least 2005 likely drove observed changes in the proportion and age distribution of wild-type native prion protein (PRNP) gene homozygotes among deer sampled. Predation by mountain lions (Puma concolor) may be helping keep CWD in check. Despite stable appearances, prion disease nonetheless impairs adult survival and likely resilience in this deer herd, limiting its potential for growth despite refuge from hunter harvest and favorable habitat and winter conditions.

Efficacy and safety of gout flare prophylaxis and therapy use in people with chronic kidney disease: a Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN)-initiated literature review.

Gout flare prophylaxis and therapy use in people with underlying chronic kidney disease (CKD) is challenging, given limited treatment options and risk of worsening renal function with inappropriate treatment dosing. This literature review aimed to describe the current literature on the efficacy and safety of gout flare prophylaxis and therapy use in people with CKD stages 3-5. A literature search via PubMed, the Cochrane Library, and EMBASE was performed from 1 January 1959 to 31 January 2018. Inclusion criteria were studies with people with gout and renal impairment (i.e. estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) < 60 ml/min/1.73 m2), and with exposure to colchicine, interleukin-1 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids. All study designs were included. A total of 33 studies with efficacy and/or safety analysis stratified by renal function were reviewed-colchicine (n = 20), anakinra (n = 7), canakinumab (n = 1), NSAIDs (n = 3), and glucocorticoids (n = 2). A total of 58 studies reported these primary outcomes without renal function stratification-colchicine (n = 29), anakinra (n = 10), canakinumab (n = 6), rilonacept (n = 2), NSAIDs (n = 1), and glucocorticoids (n = 10). Most clinical trials excluded study participants with severe CKD (i.e. eGFR or CrCl of < 30 mL/min/1.73 m2). Information on the efficacy and safety outcomes of gout flare prophylaxis and therapy use stratified by renal function is lacking. Clinical trial results cannot be extrapolated for those with advanced CKD. Where possible, current and future gout flare studies should include patients with CKD and with study outcomes reported based on renal function and using standardised gout flare definition.

EVALUATION OF TWO MEDETOMIDINE-AZAPERONE-ALFAXALONE COMBINATIONS IN CAPTIVE ROCKY MOUNTAIN ELK (CERVUS ELAPHUS NELSONI).

Alfaxalone has been successfully used intramuscularly (im) combined with medetomidine and azaperone for immobilization of small ungulates. An experimental 40 mg/ml alfaxalone solution (RD0387) was recently formulated for reduced injection volume. The objective of this study was to assess the efficacy and cardiopulmonary effects of high-concentration alfaxalone combined with medetomidine and azaperone for the intramuscular immobilization of captive Rocky Mountain elk (Cervus elaphus nelsoni). Seven adult female elk were used in a crossover design in which they were administered alfaxalone 1 mg/kg, medetomidine 0.05 mg/kg, and azaperone 0.1 mg/kg or alfaxalone 0.5 mg/kg, medetomidine 0.1 mg/kg, and azaperone 0.1 mg/kg im approximately 3 wk apart. Drugs were delivered to each elk in a chute by hand injection. Once recumbent, elk were placed in sternal recumbency for a period of 30 min, during which time level of sedation, response to minor procedures, heart rate, respiratory rate, rectal temperature, oxygen saturation, and direct arterial blood pressures were recorded every 5 min. Arterial blood gases were performed every 15 min. At 30 min, elk were administered atipamezole 0.25 or 0.5 mg/kg im and recovery quality and times were recorded. Statistical comparisons were made by t test, Wilcoxon signed rank test, and repeated measures analysis (significance level P < 0.05). Both drug combinations provided effective immobilization for 30 min, with induction and recovery time and quality similar to other medetomidine-based combinations used in elk. Cardiopulmonary effects included bradycardia, hypertension, and hypoxemia that resolved with oxygen supplementation. The average injection volume in the low-dose alfaxalone combination was approximately 5 ml. These combinations provided deep sedation and the ability to perform minor procedures in captive elk, with acceptable cardiopulmonary parameters as long as supplemental oxygen was provided.

Colchicine Use and Incident Coronary Artery Disease in Male Patients With Gout.

BACKGROUND: Inflammation is associated with coronary artery disease (CAD) and myocardial infarction (MI). Patients with gout are at increased risk of MI, and colchicine is associated with a reduced risk of MI. The objective of this study was to determine whether colchicine prevents incident development of CAD in patients with gout. METHODS: This retrospective study followed a cohort of male patients with gout without known CAD at the time of diagnosis of gout in the VA New York Harbor Healthcare System. The association between colchicine use and development of incident CAD, defined as evidence of ischemia or obstructive CAD on stress test or angiography, was determined using an inverse probability weighted (IPW) Cox proportional hazard model. RESULTS: Among 178,877 patients, 1638 met criteria of gout, of whom 722 without known CAD at baseline (446 colchicine users and 276 nonusers) were followed for a median of 96 months (57 to 117). A trend toward association between use of colchicine and reduced incident CAD was observed but not statistically significant (IPW hazard ratio [HR], 0.49; 0.23-1.05). In patients without chronic kidney disease, use of colchicine was associated with a lower rate of incident CAD (interaction P = 0.005, IPW HR, 0.31; 0.14-0.70). Colchicine was also associated with a lower rate of the composite of incident CAD and MI (IPW HR, 0.37; 0.16-0.83). CONCLUSIONS: In male patients with gout and no known CAD, a trend of reduced incident CAD was observed with use of colchicine that was not statistically significant. Larger, prospective studies will be required to assess the primary prevention benefit of colchicine definitively.

Tissue Residue Levels of the Tranquilizer Combination of Butorphanol, Azaperone, and Medetomidine, and the Antagonists, Naltrexone, Atipamezole, and Tolazoline, in Black Bears (Ursus americanus) Postimmobilization.

The tranquilizer combination of butorphanol, azaperone, and medetomidine (BAM) has shown good efficacy for immobilization of wildlife, including black bears (Ursus americanus). BAM is antagonized with a combination of naltrexone and atipamezole. We immobilized 19 adult captive wild caught black bears and, except for three bears that were euthanized immediately, bears were recovered with naltrexone and atipamezole. Tissue residues (≥0.01 ppm) for the tranquilizers butorphanol, azaperone, and medetomidine were detected in liver and muscle of all three bears euthanized on day 0 postinjection (PI). Azaperone was not detected after 1 d PI. Residue for medetomidine was detected in two bears: in the liver 3 d PI and in the kidney 6 d PI. Butorphanol was reported in three bears: in fat 5 d PI, in kidney 6 d PI, and, surprisingly, in kidney, muscle, and fat 7 d PI. No tissue residues were detected in the three bears euthanized at 8 d PI. Tissue residues for the antagonists, naltrexone and atipamezole, were detected in bears euthanized 2 and 6 d PI, but not in tissues from animals euthanized at 7 or 8 d PI.

Blocking extracellular Galectin-3 in patients with osteoarthritis.

OBJECTIVE: This pilot clinical trial examined the efficacy of blocking extracellular Galectin-3 (Gal-3) with modified citrus pectin (MCP), in patients suffering from knee osteoarthritis (OA). METHODS: 50 patients were randomized in a 1:1 ratio to receive MCP or placebo at a dose of 4 g (5 capsules) twice daily for 12 weeks. Serum Gal-3 levels and OA severity were evaluated at baseline and 12 weeks. Gal-3 levels were detected by sandwich ELISA and OA severity was determined using WOMAC-knee, SF-36, and RAPID3 surveys during these visits. MCP tolerability was assessed by a basic metabolic panel during a week 6 follow up visit. RESULTS: Patients enrolled in both the MCP treatment and placebo groups shared similar baseline characteristics in OA severity, serum Gal-3 levels, and pain management. Improvement across all surveys was noted independent of supplement or placebo treatment. No significant change in Gal-3 levels were observed in either cohort over the 12-week study. CONCLUSION: Treatment of knee OA with a 12-week course of MCP did not significantly improve disease burden compared to placebo.

Low-Dose Allopurinol Promotes Greater Serum Urate Lowering in Gout Patients with Chronic Kidney Disease Compared with Normal Kidney Function.

OBJECTIVES: Gout patients with chronic kidney disease (CKD) accumulate the active allopurinol metabolite oxypurinol, suggesting that allopurinol may promote greater serum urate (sU) lowering in CKD patients. METHODS: We identified all patientswith gout diagnoses on either 100 mg or 300 mg of allopurinol daily, with available pre- and on-treatment sU levels, in our system in a 1-year period. Mean sU decrement by dosing per CKD groups was determined by CKD stage. RESULTS: Of 1,288 subjects with gout, 180 met entry criteria, with 83 subjects receiving 100 mg and 97 receiving 300 mg allopurinol. Subjects with CKD stage 1 experienced less sU lowering with 100 mg than 300 mg of allopurinol. Subjects with stage 4 and 5 CKD had equivalent sU decreases across the 100 mg and 300 mg allopurinol groups. However, the 100 mg group started at a higher pre-treatment sU and ended at a higher final sU than the 300 mg group. CONCLUSIONS: The strategy of titrating allopurinol to sU in patients with kidney impairment may result in greater sU lowering at lower doses than in patients without CKD but may also pose a treatment challenge from a possible drug ceiling effect.

Gout, Hyperuricemia, and Crystal-Associated Disease Network Consensus Statement Regarding Labels and Definitions for Disease Elements in Gout.

OBJECTIVE: The language currently used to describe gout lacks standardization. The aim of this project was to develop a consensus statement on the labels and definitions used to describe the basic disease elements of gout. METHODS: Experts in gout (n = 130) were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach consensus on the labeling and definitions for the basic disease elements of gout. Disease elements and labels in current use were derived from a content analysis of the contemporary medical literature, and the results of this analysis were used for item selection in the Delphi exercise and face-to-face consensus meeting. RESULTS: There were 51 respondents to the Delphi exercise and 30 attendees at the face-to-face meeting. Consensus agreement (≥80%) was achieved for the labels of 8 disease elements through the Delphi exercise; the remaining 3 labels reached consensus agreement through the face-to-face consensus meeting. The agreed labels were monosodium urate crystals, urate, hyperuric(a)emia, tophus, subcutaneous tophus, gout flare, intercritical gout, chronic gouty arthritis, imaging evidence of monosodium urate crystal deposition, gouty bone erosion, and podagra. Participants at the face-to-face meeting achieved consensus agreement for the definitions of all 11 elements and a recommendation that the label "chronic gout" should not be used. CONCLUSION: Consensus agreement was achieved for the labels and definitions of 11 elements representing the fundamental components of gout etiology, pathophysiology, and clinical presentation. The Gout, Hyperuricemia, and Crystal-Associated Disease Network recommends the use of these labels when describing the basic disease elements of gout.

EVALUATION OF CHEMICAL IMMOBILIZATION IN CAPTIVE BLACK BEARS ( URSUS AMERICANUS) RECEIVING A COMBINATION OF NALBUPHINE, MEDETOMIDINE, AND AZAPERONE.

To assess potential seasonal differences in responses to immobilization, we sedated eight orphaned yearling black bears ( Ursus americanus) being held for rehabilitation at a wildlife facility in Colorado, US, using a premixed combination of nalbuphine (40 mg/mL), azaperone (10 mg/mL), and medetomidine (10 mg/mL; NalMed-A) in October (autumn) prior to hibernation and again after emergence in May (spring) prior to their release. We dosed all bears at 1 mL NalMed-A per estimated 45 kg body mass (1 mL NalMed-A/45 kg), delivered by intramuscular injection using a pole syringe, to facilitate routine examination and ear tagging. Arterial blood gases were measured to assess oxygenation and acid-base status of bears both pre and post oxygen supplementation. The mean (SE) dose calculated post hoc was 0.9 (0.04) mg nalbuphine/kg, 0.2 (0.01) mg azaperone/kg, and 0.2 (0.01) mg medetomidine/kg. The mean induction time was 8 (1) min for six of the bears in October and 6 (1) min for eight bears in May. The NalMed-A combination provided good sedation in captive yearling black bears in autumn and spring and was effectively antagonized with a combination of naltrexone and atipamezole. Mild hypoxemia (PaO2: 53.5-54.4 mmHg) was the most significant side effect and was corrected (PaO2: 68.4-150.1 mmHg) with supplemental oxygen administered at 2-5 L/min for 5 min (point of sampling).

Tissue Residue Levels after Immobilization of Rocky Mountain Elk ( Cervus elaphus nelsoni) using a Combination of Nalbuphine, Medetomidine, and Azaperone Antagonized with Naltrexone, Atipamezole, and Tolazoline.

Previous studies demonstrated that nalbuphine, medetomidine, and azaperone (NalMed-A) can effectively immobilize adult elk ( Cervus elaphus nelsoni), and be antagonized using naltrexone and atipamezole, with or without tolazoline. To assess duration of tissue residues for this immobilization package, we immobilized 14 captive adult elk with NalMed-A, then euthanized animals and collected tissues 0, 3, 6, 14, 21, or 28 d later. Except for two animals euthanized immediately, all elk were recovered using naltrexone, atipamezole, and tolazoline. Tissue residues (≥0.01 parts per million) for the tranquilizers nalbuphine, medetomidine, and azaperone were detected in liver and muscle tissue samples from elk euthanized within 40 min postinjection (PI) and one animal that died 12-24 h PI, but not in tissues from any of the animals euthanized at 3, 6, 14, 21, or 28 d PI. Tissue residues for the antagonists naltrexone, atipamezole, and tolazoline were detected in liver and muscle of the animal that died 12-24 h PI. Only naltrexone was detected in liver from the two elk euthanized at day 3, and no antagonist residues were detected thereafter.

Survival benefit of statin use in ankylosing spondylitis: a general population-based cohort study.

OBJECTIVES: Recent studies have shown an increase in both cardiovascular and all-cause mortality in ankylosing spondylitis (AS). We examined the potential survival benefit of statin use in AS within a general population context. METHODS: We performed an incident user cohort study with time-stratified propensity score matching using a UK general population database between 1 January 2000 and 31 December 2014. To account for potential confounders, we compared propensity score-matched cohorts of statin initiators and non-initiators using 1-year cohort accrual blocks. The variables used to create the propensity score model included disease duration, body mass index, lifestyle factors, comorbidities and medication use. RESULTS: Using unmatched AS cohorts, statin initiators (n=1430) showed a 43% higher risk of mortality than non-initiators (n=1430) (HR=1.43; 95% CI 1.12 to 1.84). After propensity score matching, patients with AS who initiated statins (n=1108) had 96 deaths, and matched non-initiators (n=1108) had 134 deaths over a mean follow-up of 5.3 and 5.1 years, respectively. This corresponded to mortality rates of 16.5 and 23.8 per 1000 person-years (PY), respectively, resulting in an HR of 0.63 (95% CI 0.46 to 0.85) and an absolute mortality rate difference of 7.3 deaths per 1000 PY (95% CI 2.1 to 12.5). CONCLUSION: This general population-based cohort study suggests that statin initiation is associated with a substantially lower risk of mortality among patients with AS. The magnitude of the inverse association appears to be larger than that observed in randomised trials of the general population and in population-based cohort studies of patients with rheumatoid arthritis.

The unclosing premature mortality gap in gout: a general population-based study.

OBJECTIVE: Gout, the most common inflammatory arthritis, is associated with premature mortality. Whether this mortality gap has improved over time, as observed in rheumatoid arthritis (RA), is unknown. METHODS: Using an electronic medical record database representative of the UK general population, we identified incident gout cases and controls between 1999 and 2014. The gout cohort was divided based on year of diagnosis into early (1999-2006) and late (2007-2014) cohorts. We compared the mortality rates and HRs, adjusting for potential confounders between the cohorts. We conducted sensitivity analyses among patients with gout who received at least one prescription for urate-lowering therapy, which has been found to have a validity of 90%. RESULTS: In both cohorts, patients with gout showed similar levels of excess mortality compared with their corresponding comparison cohort (ie, 29.1 vs 23.5 deaths/1000 person-years and 23.0 vs 18.8 deaths/1000 person-years in the early and late cohorts, respectively). The corresponding mortality HRs were 1.25 (95% CI 1.21 to 1.30) and 1.24 (95% CI 1.20 to 1.29), and the multivariable HRs were 1.10 (95% CI 1.06 to 1.15) and 1.09 (95% CI 1.05 to 1.13), respectively (both p values for interaction >0.72). Our sensitivity analyses showed similar findings (both p values for interaction >0.88). CONCLUSIONS: This general population-based cohort study indicates that the level of premature mortality among patients with gout remains unimproved over the past 16 years, unlike RA during the same period. This unclosing premature mortality gap calls for improved management of gout and its comorbidities.

THE EFFICACY OF NALBUPHINE, MEDETOMIDINE, AND AZAPERONE IN IMMOBILIZING AMERICAN BISON (BISON BISON).

We evaluated a combination of nalbuphine, medetomidine, and azaperone (NalMed-A) in 12 American bison ( Bison bison ) during 13 sedation handling events. The mean (SE) dosage was 0.4 (0.02) mg/kg nalbuphine, 0.08 (0.003) mg/kg medetomidine, and 0.08 (0.003) mg/kg azaperone contained in an average delivery volume of 0.8 mL/100 kg. Two animals required a supplemental dose for safe handling (additive dose used in calculating means) and a third animal was not adequately sedated despite a supplemental dose. Bison immobilized with NalMed-A showed good sedation in 12 of 13 handling attempts. Advantages of this drug combination included a relatively low delivery volume, rapid antagonism, and minimal regulatory burden for component drugs. The most consistent disadvantage was hypoxemia, and oxygen supplementation is recommended when using this sedative combination in bison.

Use of acepromazine and medetomidine in combination for sedation and handling of Rocky Mountain elk (Cervus elaphus nelsoni) and black bears (Ursus americanus).

We opportunistically evaluated a combination of acepromazine maleate and medetomidine HCl for use in sedating Rocky Mountain elk (Cervus elaphus nelsoni) and black bears (Ursus americanus) as an alternative to scheduled drug combinations. This combination was safe and effective with limitations inherent in its sedative rather than anesthetic properties.

Efficacy of a low-dosage combination of butorphanol, azaperone, and medetomidine (BAM) to immobilize Rocky Mountain elk.

We compared dosages of a combination of sedatives, which included butorphanol tartrate, azaperone tartrate, and medetomidine HCl (BAM) in captive adult Rocky Mountain elk (Cervus elaphus nelsoni). All three BAM dosages (low, medium, and high) effectively immobilized elk and produced an adequate level of sedation in all subjects. Induction times were similar among the three groups (mean ± SD: low=6.9 ± 1.1 min; medium=6.3 ± 0.9 min; high=4.7 ± 1.3 min). Most elk became hypoxemic regardless of BAM dosage, but hypoxemia tended to be most severe in the high-BAM group; regardless of BAM dosage, oxygen supplementation improved the percentage of oxygen saturation and stabilized the vital rates. Recovery after administration of antagonists (3 mg atipamezole/mg medetomidine and 2 mg/kg tolazoline) was comparable among groups (range of means=9 ± 1.5-11.7 ± 1 min). Based on the findings from clinical trials and field data from free-ranging elk immobilizations, we recommend low-dose BAM (2 mL dose; equivalent to 46 mg butorphanol, 30 mg azaperone, and 18 mg medetomidine) and supplemental oxygen for adult elk; immobilization should be antagonized using 3-5 mg atipamezole/mg medetomidine and 2 mg/kg tolazoline, with tolazoline injected about 5-10 min before atipamezole to smooth out recovery.

A comparison of the malignancy incidence among patients with psoriatic arthritis and patients with rheumatoid arthritis in a large US cohort.

OBJECTIVE: To compare the incidence rates of malignancy among patients with psoriatic arthritis (PsA) and patients with rheumatoid arthritis (RA) in the Consortium of Rheumatology Researchers of North America (CORRONA) registry. METHODS: We analyzed 2,970 patients with PsA (7,133 patient-years of followup) and 19,260 patients with RA (53,864 patient-years of followup). Using a standardized adjudication process, we identified 40 confirmed malignancies in the patients with PsA and 307 confirmed malignancies in those with RA. Incidence rates were calculated per 100 patient-years. Incidence rate ratios were estimated, with adjustment for age, sex, disease duration, body mass index, disease activity, year of enrollment, and medication use. RESULTS: The overall malignancy incidence per 100 patient-years was similar between patients with PsA and patients with RA (0.56 [95% confidence interval (95% CI) 0.40-0.76] and 0.56 [95% CI 0.50-0.63], respectively). Nonmelanoma skin cancer was the most common type of cancer in the overall cohort, with an incidence rate of 0.21 (95% CI 0.12-0.35) in PsA, and 0.20 (95% CI 0.17-0.24) in RA, with a calculated incidence rate ratio of 1.05 (95% CI 0.61-1.80; P = 0.85). Lymphoma rates were similar in PsA and RA (0.04 [95% CI 0.01-0.12] and 0.04 [95% CI 0.02-0.06], respectively; incidence rate ratio 1.00 [95% CI 0.17-3.11]; P = 0.67). The adjusted incidence rate ratio of malignancy in PsA versus RA was 1.17 (95% CI 0.82-1.69; P = 0.37). CONCLUSION: The incidence rates across malignancy subtypes were similar in the PsA and RA cohorts from a US registry.

Clinical correlations with Porphyromonas gingivalis antibody responses in patients with early rheumatoid arthritis.

INTRODUCTION: Prior studies have demonstrated an increased frequency of antibodies to Porphyromonas gingivalis (Pg), a leading agent of periodontal disease, in rheumatoid arthritis (RA) patients. However, these patients generally had long-standing disease, and clinical associations with these antibodies were inconsistent. Our goal was to examine Pg antibody responses and their clinical associations in patients with early RA prior to and after disease-modifying antirheumatic drug (DMARD) therapy. METHODS: Serum samples from 50 DMARD-naïve RA patients were tested using an enzyme-linked immunosorbent assay with whole-Pg sonicate. For comparison, serum samples were tested from patients with late RA, patients with other connective tissue diseases (CTDs), age-similar healthy hospital personnel and blood bank donors. Pg antibody responses in early RA patients were correlated with standard RA biomarkers, measures of disease activity and function. RESULTS: At the time of enrollment, 17 (34%) of the 50 patients with early RA had positive immunoglobulin G (IgG) antibody responses to Pg, as did 13 (30%) of the 43 patients with late RA. RA patients had significantly higher Pg antibody responses than healthy hospital personnel and blood bank donors (P < 0.0001). Additionally, RA patients tended to have higher Pg antibody reactivity than patients with other CTDs (P = 0.1), and CTD patients tended to have higher Pg responses than healthy participants (P = 0.07). Compared with Pg antibody-negative patients, early RA patients with positive Pg responses more often had anti-cyclic citrullinated peptide (anti-CCP) antibody reactivity, their anti-CCP levels were significantly higher (P = 0.03) and the levels of anti-Pg antibodies correlated directly with anti-CCP levels (P < 0.01). Furthermore, at the time of study entry, the Pg-positive antibody group had greater rheumatoid factor values (P = 0.04) and higher inflammatory markers (erythrocyte sedimentation rate, or ESR) (P = 0.05), and they tended to have higher disease activity scores (Disease Activity Score based on 28-joint count (DAS28)-ESR and Clinical Disease Activity Index) and more functional impairment (Health Assessment Questionnaire). In Pg-positive patients, greater disease activity was still apparent after 12 months of DMARD therapy. CONCLUSIONS: A subset of early RA patients had positive Pg antibody responses. The responses correlated with anti-CCP antibody reactivity and to a lesser degree with ESR values. There was a trend toward greater disease activity in Pg-positive patients, and this trend remained after 12 months of DMARD therapy. These findings are consistent with a role for Pg in disease pathogenesis in a subset of RA patients.