Evaluating health benefits and cost-effectiveness of a mass-media campaign for improving participation in the National Bowel Cancer Screening Program in Australia.

OBJECTIVES: The Australian National Bowel Cancer Screening Program (NBCSP) offers free 2-yearly immunochemical faecal occult blood testing to individuals aged 50-74 years; national participation in 2015-2016 was 41%. In 2017, a 7-week television-led mass-media campaign to increase participation in the Australian state of Victoria was associated with a 1.31-fold increase in participation for 11 weeks. We aimed to evaluate the cost-effectiveness and health benefits of the 2017 campaign and scaled-up equivalent campaigns run over 4 years in Victoria and nationally. STUDY DESIGN: This study used microsimulation modelling. METHODS: A comprehensive microsimulation model of colorectal cancer (CRC), Policy1-Bowel, was used to simulate three scenarios. Scenario 1 simulated the 2017 campaign in Victoria; Scenarios 2 and 3 assumed that campaigns were run three times annually from 2019 to 2022 in Victoria and Australia-wide, respectively. Total campaign costs of AUD$1million, AUD$10million, and AUD$40million were assumed for Scenarios 1, 2, and 3, respectively. The incremental effects and costs of the campaign on the NBCSP were assessed. A governmental perspective was used. RESULTS: All campaign scenarios were predicted to be highly cost-effective, with cost-effectiveness ratios under AUD$4,800/life-year saved. The actual 2017 campaign in Victoria is estimated to prevent 319 CRC cases and 183 deaths over the following 40 years. A 4-year campaign would prevent 1,750 CRC cases and 987 deaths if conducted in Victoria, and 8,100 cases and 4,330 deaths if conducted Australia-wide. CONCLUSION: Mass-media participation campaigns could be highly cost-effective and maximise the potential life-saving impact of bowel screening. These results support ongoing investment in major bowel screening campaigns.

Development of a perceived exertion scale for dogs using selected physiologic parameters.

OBJECTIVE: To develop a perceived exertion scale for dogs exercising on a treadmill and to assess intra- and inter-observer variability. MATERIALS AND METHODS: Fifteen healthy client-owned dogs participated in paired exercise trials. Measurements of lactate, glucose, heart rate, temperature, respiratory rate and regional tissue oximetry were obtained before, during and after exercise. Perceived exertion scale scores were recorded during exercise and using video recordings to evaluate inter-observer variability. Correlations were evaluated using the Spearman's non-parametric method. RESULTS: Thirteen dogs completed both trials. Dogs walked or trotted on the treadmill with an average perceived exertion score of 2 in both trials. Holter heart rate was positively correlated with perceived exertion scale scores from all observers for both trials. In trial 1, plasma glucose decreased in association with increase in perceived exertion and, in trial 2, cutaneous oximetry decreased, respiratory rate increased and temperature increased with increases on the perceived exertion scale. Inter-observer perceived exertion scale scores were positively correlated in both trials. There was no intra-observer variability between trials. CLINICAL SIGNIFICANCE: The perceived exertion scale correlated with the measured physiologic parameters in dogs exercising at mild to moderate intensity. The perceived exertion scale was consistent and repeatable but larger study numbers and further validation are needed before it can be widely applied.

Effects of dietary calcium fructoborate supplementation on joint comfort and flexibility and serum inflammatory markers in dogs with osteoarthritis.

Our objective was to evaluate the short-term effects of calcium fructoborate (CFB) on gait, joint range of motion, serum inflammatory markers, and owner perception of pain in client-owned dogs. We used 59 osteoarthritic dogs with impairment, with dogs being randomly assigned to 4 treatments: placebo (60 mg fructose; = 15), low dose (69 mg CFB; = 14), high dose (127 mg CFB; = 14), or combination (69 mg CFB, 500 mg glucosamine hydrochloride and 200 mg chondroitin sulfate; = 16). Dogs up to 22.9 kg received 1 capsule/d, while dogs weighing 23 to 50 kg received 2 capsules/d. A physical examination, radiographs, goniometry measurements, gait analysis, blood sample collection, and a canine brief pain inventory questionnaire were performed on d 0 and 28. Change from baseline values were statistically analyzed among groups. After 28 d, dogs fed the low and high doses had an improved ( < 0.05) ability to rise from a lying position compared to placebo. Dogs fed the high dose also had a greater ( = 0.05) increase in soluble receptor for advanced glycation end products concentration than dogs fed the placebo. Sub-analysis of only large dogs (> 23 kg) showed that dogs fed the low dose had decreased ( < 0.05) pain severity score and pain at its worst compared to dogs fed the placebo. Large dogs fed the low dose also were shown to improve ( < 0.05) in their ability to rise from a lying position compared to dogs fed the placebo. Overall, CFB supplementation was well-tolerated and may aid in mitigating joint discomfort in dogs.

Barbed versus smooth poly-propylene three-loop pulley sutures for repair of canine gastrocnemius tendon.

OBJECTIVE: To compare the ultimate tensile strength (UTS) and load to 1 and 3 mm gap formation of smooth (3-metric) and knotless barbed (4-metric) polypropylene sutures placed in a three-loop pulley pattern for canine gastrocnemius tendon repair. STUDY DESIGN: In vitro. SAMPLE SIZE: Thirty-three paired bone-tendon units with one of each pair assigned to each suture type. Barbed suture size was based on previously published materials testing results. METHODS: Each unit was placed in a servo-hydraulic testing machine and tested under single cycle tensile loading until repair failure. RESULTS: There was a significantly higher UTS for smooth polypropylene compared to the barbed polypropylene repairs. The loads resulting in 1 and 3 mm gaps for the barbed repairs were consistently significantly less than the corresponding smooth polypropylene repair values. CONCLUSION: The knotted smooth polypropylene repair was consistently stronger than the knotless barbed polypropylene repair when placed in a three-loop pulley pattern for gastrocnemius repair. CLINICAL SIGNIFICANCE: Knotless barbed polypropylene suture should not be considered equivalent to knotted smooth polypropylene of comparable tensile strength when placed in a three-loop pulley pattern for canine gastrocnemius tendon repair. The low failure loads of the barbed repair are probably due to failure of the barbs to anchor consistently throughout the tendon in the knotless configuration.

The effects of a novel lateral extracapsular suture system on the kinematics of the cranial cruciate deficient canine stifle.

OBJECTIVE: To evaluate the relative position of the femur and tibia in cranial cruciate ligament-intact stifles, cranial cruciate ligament-deficient stifles, and cruciate-deficient stifles following lateral extracapsular suture system (LESS) stabilization under load at specific joint angles. STUDY DESIGN: In vitro biomechanical study. METHODS: Twenty pelvic limbs from 11 dogs were used to evaluate the relative position of the femur and tibia between three stifle conditions (cranial cruciate ligament-intact, cranial cruciate ligament-deficient, and LESS-stabilized) at a load of 30% of body weight and stifle angles of 125°, 135°, and 145° using electromagnetic tracking sensors. RESULTS: Cranial cruciate ligament-deficient stifles had significantly greater (p <0.0001) cranial displacement and internal rotation of the tibia relative to the femur than cranial cruciate ligament-intact or LESS stifles at all stifle angles. Cranial displacement of the tibia relative to the femur for cranial cruciate ligament-intact and LESS stifles were not significantly different from one another at a stifle angle of 125°, but were significantly different at stifle angles of 135° (p = 0.0182) and 145° (p = 0.0012). There was no significant difference in internal rotation of the tibia relative to the femur between the cranial cruciate ligament-intact and LESS stifles at any of the stifle angles. CLINICAL SIGNIFICANCE: The LESS procedure effectively decreased cranial tibial displacement and eliminated internal rotation of the tibia relative to the femur in the cranial cruciate ligament-deficient stifles at stifle angles of 125°, 135°, and 145° in vitro.

Effect of tibial insertion site for lateral suture stabilization on the kinematics of the cranial cruciate ligament deficient-stifle during early, middle and late stance: an in vitro study.

OBJECTIVE: To evaluate the effect of two tibial attachment sites for lateral suture stabilization (LSS) on the three-dimensional femorotibial translational and rotational movements of the cranial cruciate ligament- deficient canine stifle during the early, middle and late stance phases. STUDY DESIGN: In vitro biomechanical study: 32 hindlimbs from 16 canine cadavers. METHODS: Limbs were mounted in a testing jig and an electromagnetic tracking system was used to determine the three-dimensional femorotibial translational and rotational movements under 33% of body weight load during early, middle and late stance in the following sequence: cranial cruciate ligament-intact, cranial cruciate ligament-deficient and LSS with the distal anchor through the tibial tuberosity (LSSTT) or through the cranial eminence of the extensor groove (LSSEG). The proximal anchor point was the lateral femorofabellar ligament. RESULTS: Post-LSS stifle three-dimensional femorotibial translational and rotational movements were more comparable to normal than post-transection movements for both techniques. Both LSS techniques restored femorotibial movements in cranial cruciate ligament-deficient stifles to varying amounts but neither technique successfully restored normal three-dimensional femorotibial movements. The LSSEG improved femorotibial movements of the cranial cruciate ligament-deficient stifle in the medial-lateral direction and axial rotation but performed poorly in restoring femorotibial movements in the cranial-caudal direction as compared to the LSSTT. CLINICAL SIGNIFICANCE: Both the LSSTT and LSSEG techniques failed to completely restore normal three-dimensional femorotibial translational and rotational movements in cranial cruciate ligament-deficient stifles in vitro.

Guided imagery to improve functional outcomes post-anterior cruciate ligament repair: randomized-controlled pilot trial.

Imagery can improve functional outcomes post-anterior cruciate ligament repair (ACLR). Research is needed to investigate potential mechanisms for this effect. The aim of this study was to (a) evaluate the effectiveness of an imagery intervention to improve functional outcomes post-ACLR, and (b) explore potential mechanisms. A randomized-controlled pilot trial was conducted. Participants were randomized to guided imagery and standard rehabilitation or standard rehabilitation alone (control). The primary outcome was knee strength 6-month post-operatively. Secondary outcomes were knee laxity at 6-months, and change in psychological (self-efficacy) and neurohormonal (adrenaline, noradrenaline, dopamine) variables. Participants (n=21; 62% male) were 34.86 (SD 8.84) years. Following the intervention, no statistical differences between groups for knee strength extension at 180°/s (t=-0.43, P=0.67), or at 60°/s (t=-0.72, P=0.48) were found. A statistically significant effect was found for knee laxity, F=4.67, P<0.05, mean difference of -3.02 (95% CI -4.44 to -1.60), favoring the intervention. No differences were found for self-efficacy; however, an overall effect was found for noradrenaline, F(1, 19) 19.65, P<0.001, η(2) =0.52, and dopamine, F(1, 19) 6.23, P=0.02, η(2) =0.29, favoring the intervention. This imagery intervention improved knee laxity and healing-related neurobiological factors.

1-Aminobenzotriazole, a known cytochrome P450 inhibitor, is a substrate and inhibitor of N-acetyltransferase.

1-Aminobenzotriazole (ABT) has been used widely as a nonselective in vitro and in vivo inhibitor of cytochrome P450 enzymes. To date, however, it has not been evaluated as an inhibitor of UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and N-acetyltransferase (NAT). In the present study, ABT was shown not to inhibit UGT and SULT activity (acetaminophen and 7-hydroxycoumarin as substrates) in rat liver microsomes and rat liver 9000 g supernatant fraction (RLS9), respectively. However, it did inhibit the RLS9-catalyzed N-acetylation of procainamide (IC(50) ∼ 30 µM), and no preincubation time dependence was evident. In agreement, oral ABT (100 mg/kg, 2 h predose) decreased the clearance of intravenous procainamide (45%) in rats, accompanied by a decreased N-acetylprocainamide-to-procainamide ratio in urine (0.74 versus 0.21) and plasma (area under the curve ratio 0.59 versus 0.11). Additional studies with human forms of NAT (hNAT1 and hNAT2) revealed that ABT is a more potent inhibitor of hNAT2 compared with hNAT1 (IC(50) 158 µM versus > 1 mM). Consistent with the IC(50) estimate, formal inhibition studies revealed that inhibition of hNAT2 was competitive with an inhibition constant of 67 µM. In accordance with the competitive inhibition, ABT was shown to undergo N-acetylation in the presence of both human NAT forms, with hNAT1 exhibiting less activity under the same assay conditions (∼40% of hNAT2). In summary, the results described herein indicate that ABT is a substrate and inhibitor of NAT. Such an interaction should be considered when using ABT as a nonselective inhibitor of P450, especially when NAT-dependent metabolism is also involved.

Effect of stifle angle on the magnitude of the tibial plateau angle measurement in dogs with intact and transected cranial cruciate ligament. A cadaveric study.

OBJECTIVE: To determine the effect of stifle angle on the magnitude of the radiographic tibial plateau angle (TPA) in normal and cranial cruciate ligament (CCL) -deficient stifles. METHODS: Three pairs of canine cadaver hindlimbs from three skeletally mature dogs were positioned in a custom-made positioning device. A lateral radiograph of each specimen was obtained before and after transection of the CCL at four stifle angles (90°, 110°, 135° and 140-150° [i.e. maximum extension]), based on goniometric measurements. Four observers determined the radiographic TPA twice for each radiograph with a minimum of two days between each measurement. The radiographic TPA measurements in all specimens at different stifle angles with intact CCL and transected CCL were compared with mixed-model ANOVA. The effect of stifle angle, CCL transection, and interaction between the two on observer TPA measurement variability was also determined using the coefficient of variation. RESULTS: Tibial plateau angle was not statistically different in the stifle angles for either the intact or transected CCL. There was also no statistical difference for TPA between intact and transected CCL groups at each of the stifle angles. Stifle angle, CCL transection and interaction between the two did not have any significant effect for intra-observer and inter-observer variation. CLINICAL SIGNIFICANCE: The angle of the stifle during radiography does not influence the magnitude of the TPA measurement as determined on true lateral radiographs of the stifle and tibia in cadaveric canine limbs.

Arylpropanolamines: selective beta3 agonists arising from strategies to mitigate phase I metabolic transformations.

Utilization of N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines 1 as selective beta(3) agonists is complicated by their propensity to undergo metabolic oxidative N-dealkylation, generating 0.01-2% of a very potent alpha(1) adrenergic agonist 2. A summary of the SAR for this hepatic microsomal conversion precedes presentation of strategies to maintain the advantages of chemotype 1 while mitigating the consequences of N-dealkylation. This effort led to the identification of 4-hydroxy-3-methylsulfonanilidopropanolamines 15 for which the SAR for the unique stereochemical requirements for binding to the beta adrenergic receptors culminated in the identification of the potent, selective beta(3) agonist 15f.

Why the tobacco industry fears point of sale display bans.

Banning the display of tobacco products represents a major step in tobacco control and will help to reduce tobacco sales.

BMS-201620: a selective beta 3 agonist.

A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were prepared and evaluated for their human beta3 adrenergic receptor agonist activity. SAR studies led to the identification of BMS-201620 (39), a potent beta3 full agonist (Ki = 93 nM, 93% activation). Based on its favorable safety profile, BMS-201620 was chosen for clinical evaluation.

Smoking and gambling: a trance inducing ritual.

"Smoking is a powerful re-inforcement for the trance-inducing rituals associated with gambling."

Medicinal and ethnoveterinary remedies of hunters in Trinidad.

BACKGROUND: Ethnomedicines are used by hunters for themselves and their hunting dogs in Trinidad. Plants are used for snakebites, scorpion stings, for injuries and mange of dogs and to facilitate hunting success. RESULTS: Plants used include Piper hispidum, Pithecelobium unguis-cati, Bauhinia excisa, Bauhinia cumanensis, Cecropia peltata, Aframomum melegueta, Aristolochia rugosa, Aristolochia trilobata, Jatropha curcas, Jatropha gossypifolia, Nicotiana tabacum, Vernonia scorpioides, Petiveria alliacea, Renealmia alpinia, Justicia secunda, Phyllanthus urinaria,Phyllanthus niruri,Momordica charantia, Xiphidium caeruleum, Ottonia ovata, Lepianthes peltata, Capsicum frutescens, Costus scaber, Dendropanax arboreus, Siparuma guianensis, Syngonium podophyllum, Monstera dubia, Solanum species, Eclipta prostrata, Spiranthes acaulis, Croton gossypifolius, Barleria lupulina, Cola nitida, Acrocomia ierensis (tentative ID). CONCLUSION: Plant use is based on odour, and plant morphological characteristics and is embedded in a complex cultural context based on indigenous Amerindian beliefs. It is suggested that the medicinal plants exerted a physiological action on the hunter or his dog. Some of the plants mentioned contain chemicals that may explain the ethnomedicinal and ethnoveterinary use. For instance some of the plants influence the immune system or are effective against internal and external parasites. Plant baths may contribute to the health and well being of the hunting dogs.

Design and synthesis of 4-substituted benzamides as potent, selective, and orally bioavailable I(Ks) blockers.

Multiple delayed rectifier potassium currents, including I(Ks), are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent I(Ks) blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

BMS-196085: a potent and selective full agonist of the human beta(3) adrenergic receptor.

A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.

In situ synthesis of oligonucleotide arrays by using surface tension.

This work describes the in situ synthesis of oligonucleotide arrays on glass surfaces. These arrays are composed of features defined and separated by differential surface tension (surface tension arrays). Specifically, photolithographic methods were used to create a series of spatially addressable, circular features containing an amino-terminated organosilane coupled to the glass through a siloxane linkage. Each feature is bounded by a perfluorosilanated surface. The differences in surface energies between the features and surrounding zones allow for chemical reactions to be readily localized within a defined site. The aminosilanation process was analyzed using contact angle, X-ray photoelectron spectroscopy (XPS), and time-of-flight/secondary ion mass spectroscopy (TOF-SIMS). The efficiency of phosphoramidite-based oligonucleotide synthesis on these surface tension arrays was measured by two methods. One method, termed step-yields-by-hybridization, indicates an average synthesis efficiency for all four (A,G,C,T) bases of 99.9 +/- 1.1%. Step yields measured for the individual amidite bases showed efficiencies of 98.8% (dT), 98.0% (dA), 97.0% (dC), and 97.6% (dG). The second method for determining the amidite coupling efficiencies was by capillary electrophoresis (CE) analysis. Homopolymers of dT (40- and 60mer), dA (40mer), and dC (40mer) were synthesized on an NH(4)OH labile linkage. After cleavage, the products were analyzed by CE. Synthesis efficiencies were calculated by comparison of the full-length product peak with the failure peaks. The calculated coupling efficiencies were 98.8% (dT), 96.8% (dA), and 96.7% (dC).

The feasibility of a porcine model of acute coronary occlusion and reperfusion using off-pump coronary artery bypass grafting

We developed an open-chest porcine model of acute coronary occlusion and surgical reperfusion, and attempted to prevent intra-operative ischaemic ventricular fibrillation (VF) by a Retrograde Intracoronary Glyceryl trinitrate (RIG) infusion into the occluded vessel. Five Yorkshire pigs (weight 50ñ 1.1kg), randomized into 3 groups, underwent median sternotomy under general anaesthesia. One pig (Group 1, control) underwent sternotomy and pericardiotomy only. Four pigs underwent acute left anterior descending (LAD) coronary occlusion. Two pigs were not reperfused (Group 2). Two pigs underwent surgical reperfusion (Group 3) via left internal mammary artery (LIMA) grafting to the LAD using the Off-Pump Coronary Artery Bypass (OPCAB) technique. Ischaemic injury was assessed using 7-lead electrocardiography (EGG) and transthoracic/epimyocardial echocardiography (ECHO). Group 1: transient intraoperative hypotension and VF occurred. Successful resuscitation and 10-week survival (until sacrifice) with normal left ventricular (LV) function was achieved. Group 2: there were ECG and ECHO evidence of acute LV ischaemic dysfunction in both pigs. The surviving pig had persistent anterior hypokinesis at 8« months. The other died intra-operatively following progressive ischaemic LV dysfunction despite resuscitative attempts. Group 3: the surving pig had normal LV function at 8 months. Initial anterior LV akinesis normalized within 7 days. The other developed post-occlusion haemodynamic instability and died intra-operatively despite reperfusion. In this porcine model, acute LAD artery occlusion modified by the novel RIG infusion technique, followed by surgical reperfusion (OPCAB) is feasible. This model would facilitate further development of OPCAB surgical expertise and understanding of the pathophysiology of ischaemia-reperfusion injury.(Au)