Fourth Trial Research Articles

Muscle Mitochondrial Capacity Is Impaired Immediately Following Maximal Exercise.

This study measured the time course mVO2max following both maximal and submaximal exercise. Healthy male and female participants were tested (n = 12 maximal and n = 8 submaximal exercise). A NIRS device was placed on the left medial gastrocnemius. Participants performed either one minute of maximal, rapid (~2 Hz), or submaximal (~0.37 Hz) plantar flexion exercise on a custom pneumatic ergometer. mVO2max was measured before and immediately after exercise. mVO2max measurements consisted of four incomplete recovery curves of muscle metabolism taken after 30 seconds of electrical muscle stimulation except in the first post-exercise trial. The four recovery curves were collected 50-, 156-, 260-, and 366-seconds post-exercise, each producing a mVO2max rate constant. After maximal exercise muscle acceleration decreased to 52 + 18% (p = 0.001) of pre-values. mVO2max was reduced from the pre-exercise mean at the first post-trial (2.16 + 0.44 min-1 to 1.21 + 0.52 min -1, p < 0.001). The fourth trial showed recovery from the first (2.2 + 0.46 min-1 vs 1.21 + 0.52 min-1, p < 0.001) and was not significantly different from pre-exercise values (2.2 + 0.46 min-1 vs 2.16 + 0.44 min-1, p = 0.41). No change in acceleration or mVO2max was seen after submaximal exercise (p > 0.05). The 56.7% reduction in mVO2max supports the hypothesis that in young, healthy individuals a minute of maximal exercise transiently impairs mVO2max which then recovers within six minutes. The NIRS method shows promise in tracking time course changes in mVO2max and warrants further investigation of the transient effects of exercise on mVO2max.

Test-Retest Reliability and Visual Perturbation Performance Costs During 2 Reactive Agility Tasks.

High secondary injury rates after orthopedic surgeries have motivated concern toward the construct validity of return-to-sport test batteries, as it is evident that common strength and functional assessments fail to elicit pertinent behaviors like visual search and reactive decision making. This study aimed to establish the test-retest reliability of 2 reactive agility tasks and evaluate the impact of visual perturbation on physical performance. Fourteen physically active individuals completed 2 agility tasks with reaction time (ie,4 corner agility), working memory, and pathfinding (ie,color recall) components. Participants completed both tasks 4 times in 2 sessions scheduled 7days apart. Outcomes included performance metrics of reaction time, time to target, number of targets, and total time assessed with reactive training timing gates. To assess test-retest reliability, we used intraclass correlation coefficients (ICCs), standard error of measurement (SEM), and minimal detectable change (MDC). Stroboscopic goggles induced visual perturbation during the fourth trial of each task. To assess the effect of visual perturbation, we used paired t tests and calculated performance costs. The 4-corner agility task demonstrated excellent reliability with respect to reaction time (ICC3,1 = .907, SEM = 0.13, MDC = 0.35s); time to light (ICC3,1 = .935, SEM = 0.07, MDC = 0.18s); and number of lights (ICC3,1 = .800, SEM = 0.24, MDC = 0.66 lights). The color recall task demonstrated good-to-excellent test-retest reliability for time to lights (ICC3,1 = .818-.953, SEM = 0.07-0.27, MDC = 0.19-0.74s); test time (ICC3,1 = .969, SEM = 5.43, MDC = 15.04s); and errors (ICC3,1 = .882, SEM = 0.19, MDC = 0.53 errors). Visual perturbation resulted in increased time to target (P = .022-.011), number of targets (P = .039), and total test time (P = .013) representing moderate magnitude degradation of performance (d = 0.55-0.87, performance costs = 5%-12%). Both tasks demonstrated acceptable test-retest reliability. Performance degraded on both tasks with the presence of visual perturbation. These results suggest standardized reactive agility tasks are reliable and could be developed as components of dynamic RTS testing.

Assessing the impact of two forms of PACAP-38 (pituitary adenylate cyclase-activating polypeptide) on Nile tilapia (Oreochromis niloticus) immune response following challenge with Flavobacterium columnare

Antimicrobial peptides have been isolated from various organisms and play an essential role in defense against infections. They are small peptides (less than 60 amino acids) with broad-spectrum antibacterial activity. In teleosts, pituitary adenylate cyclase-activating polypeptide (PACAP) has been demonstrated to have direct antimicrobial activity against several aquatic pathogens, including those from the genus Flavobacterium. Our goal was to examine the impacts of PACAP and route of administration on the immune response of Nile tilapia (Oreochromis niloticus). Over the course of four studies, tilapia (416.1 ± 116.7 g) randomly assigned to replicate tanks were administered with either PACAP-38 or a modified form of PACAP-38 via intraperitoneal (i.p.) injection, bath, nares flush, or gill flush, and compared to PBS controls. In the first two studies, following individual treatments, tilapia underwent a bath exposure (40 L tank for 45 min) to F. columnare (isolate ALG-00-530; at 2.1 × 108 CFU/ml) or sham exposure without the addition of the bacterial culture. Fish were sampled before exposure, 48 h after stimulation, at 1 day after the onset of mortality in exposed tanks, and resolution of mortality. Tilapia that received i.p. injection of PACAP-38 showed significantly lower mortality from F. columnare (10 %) than those receiving PBS i.p. (25 %). However, bath immersion of fish, both with and without F. columnare, resulted in significant mortality due to secondary infections with Edwardsiella tarda. Administration of modified PACAP-38 via nares/gill flush, or i.p. injection did not, however, result in significantly fewer mortalities compared to sham/PBS. Furthermore, the same modified form of PACAP-38 also induced inflammatory gene expression in the spleen, and eosinophilic granule cell aggregation in the nares, following flushing. The data from the first study suggest that PACAP-38 induces protection against infection and stress mainly through a reduction of inflammatory-il1β expression. Moreover, data analysis of spleen samples from these two studies also indicates that PACAP-38 might have more anti-inflammatory impacts than its modified form. In the fourth trial, after exposing tilapia to low temperature (15–17 °C) for 30 min (cold stress), the PACAP-38 treated group had significantly lower cortisol levels compared to both PBS injected group and the negative control. Due to the observed impacts of PACAP-38 treatment on the immunophysiology of Nile tilapia, its potential for therapeutic use should be further investigated.

No difference in fat oxidation, postexercise energy expenditure or energy intake following ingestion of a protein-based breakfast compared to carbohydrate breakfast.

Background: Manipulation of macronutrient intake and exercise can alter overall energy consumption and potentially body composition. Aim: The purpose of this study was to manipulate the macronutrient content of breakfast before exercise to investigate the impact on exercise energy expenditure and postexercise energy intake (EI). Methods: Twelve active men were recruited, 11 finished the study protocol (age: 28 ± 9 years; VO2max: 56 ± 5 ml·kg-1·min-1). In a randomized crossover design, each participant completed 4 trials, 3 consisting of a specific breakfast (protein, PRO; carbohydrate, CHO; noncaloric; NON-CAL) followed in 1 h by a 45 minutes moderate intensity treadmill exercise protocol. The fourth trial consisted of breakfast and no exercise (CON). An ad-libitum lunch and food for the rest of the day were provided and assessed for EI. Measures included resting metabolic rate pre- and postbreakfast along with oxygen uptake (VO2) during and after exercise, along with hunger scales, and blood measures of glucose, insulin and plasma-PYY prebreakfast, pre-exercise, postexercise, and 60 minutes postexercise. Results: Fat oxidation was highest during exercise in the NON-CAL (0.57 g·min-1) trial with similar levels of fat oxidation between PRO (0.50 g·min-1) and CHO trials (0.48 g·min-1). Hunger was not affected by PRO intake or exercise, nor was appetite hormones and glucose. EI at lunch and dinner was not significantly different between trials. Conclusion: Pre-exercise PRO intake did not modify fat oxidation during exercise, did not lead to a larger VO2 versus CHO, nor did it attenuate EI postexercise.

Optimizing warfarin dosing for patients with atrial fibrillation using machine learning

While novel oral anticoagulants are increasingly used to reduce risk of stroke in patients with atrial fibrillation, vitamin K antagonists such as warfarin continue to be used extensively for stroke prevention across the world. While effective in reducing the risk of strokes, the complex pharmacodynamics of warfarin make it difficult to use clinically, with many patients experiencing under- and/or over- anticoagulation. In this study we employed a novel implementation of deep reinforcement learning to provide clinical decision support to optimize time in therapeutic International Normalized Ratio (INR) range. We used a novel semi-Markov decision process formulation of the Batch-Constrained deep Q-learning algorithm to develop a reinforcement learning model to dynamically recommend optimal warfarin dosing to achieve INR of 2.0–3.0 for patients with atrial fibrillation. The model was developed using data from 22,502 patients in the warfarin treated groups of the pivotal randomized clinical trials of edoxaban (ENGAGE AF-TIMI 48), apixaban (ARISTOTLE) and rivaroxaban (ROCKET AF). The model was externally validated on data from 5730 warfarin-treated patients in a fourth trial of dabigatran (RE-LY) using multilevel regression models to estimate the relationship between center-level algorithm consistent dosing, time in therapeutic INR range (TTR), and a composite clinical outcome of stroke, systemic embolism or major hemorrhage. External validation showed a positive association between center-level algorithm-consistent dosing and TTR (R2 = 0.56). Each 10% increase in algorithm-consistent dosing at the center level independently predicted a 6.78% improvement in TTR (95% CI 6.29, 7.28; p < 0.001) and a 11% decrease in the composite clinical outcome (HR 0.89; 95% CI 0.81, 1.00; p = 0.015). These results were comparable to those of a rules-based clinical algorithm used for benchmarking, for which each 10% increase in algorithm-consistent dosing independently predicted a 6.10% increase in TTR (95% CI 5.67, 6.54, p < 0.001) and a 10% decrease in the composite outcome (HR 0.90; 95% CI 0.83, 0.98, p = 0.018). Our findings suggest that a deep reinforcement learning algorithm can optimize time in therapeutic range for patients taking warfarin. A digital clinical decision support system to promote algorithm-consistent warfarin dosing could optimize time in therapeutic range and improve clinical outcomes in atrial fibrillation globally.

The Development of Learning Strategy in Reading Comprehension for Children with Hearing Impairment in Grade 4 SDLB

This research is motivated by the low understanding of children with hearing impairments in reading comprehension. Therefore, the purpose of this research is to develop strategies for teaching reading comprehension for children with hearing impairments. The method used in Mix Methods. Stages of research conducted in the hierarchy, meaning that the first stages of research will affect the research stage further in order to achieve the research objectives. The results showed that the application of learning strategy in reading comprehension has been developed effectively applied to children with hearing impairment at SLB Prima Bakti Mulya in grade 4-B, the academic year of 2015/2016. This is evident from the results of student learning has increased from the first to the fourth trial. While based on the Wilcoxon test known the value of Z count = -2, 201 with Asymp. Sig. (2-tailed) = 0.028 with a significance level (α) of 5%. Asymp Value. Sig. (2-tailed) = 0, 028 &lt;α = 0.05, then Ho is rejected and Ha accepted because Asymp value. Sig. (2-tailed) &lt;Α = 0.05

Resistance of sugarcane hybrids to internode borer Chilo sacchariphagus indicus (Lepidoptera: Crambidae)

ABSTRACT A four-year field study (2013–2016) was conducted to screen Indian sugarcane hybrids together with two susceptible checks against internode borer Chilo sacchariphagus indicus (Kapur) (Lepidoptera: Crambidae) in endemic locations of Tamil Nadu State, India. Each year, borer incidence on cane basis and intensity on internode basis were assessed at harvest to eliminate susceptible entries. Of the total 535 hybrids screened, only Co 293 emerged as resistant at the end of fourth year trial which was confirmed in tests under controlled conditions with artificial infestation. A modified relative resistance ratio computed using incidence and intensity also confirmed its resistance to the borer. In laboratory oviposition choice tests with excised leaves of the resistant Co 293 and susceptible hybrids Co 86032 and Co 1060, percent of leaf bits oviposited, egg masses laid, and egg numbers deposited were significantly lowest in Co 293. Also, an oviposition preference index computed for both egg mass number and egg number was significantly lowest for Co 293 which suggested antixenosis. Larval survival was significantly lowest in Co 293 with 5 to 10-fold higher neonate mortality than in the two susceptible hybrids. Prolonged larval development period and lower fecundity were observed when the borer was reared on Co 293 which indicated antibiosis. A relative suitability ratio developed from larval and pupal durations also indicated lower suitability of Co 293. Among the plant morphological characters examined, leaf length and cane thickness positively influenced borer incidence; loose sheath-clasp was associated with higher borer incidence. Among 12 shoot phenolics quantified, eight were present in higher quantities in Co 293 suggesting their role in antibiosis. Co 293 identified as resistant hybrid in the present study has the potential to be used as a parent in breeding programs for C. sacchariphagus indicus resistance.

Analysis of Technical Characteristics of Ren Mengqian, an Excellent Pole Vaulter

To advance the development of Chinese women's pole vaulting technique, three-dimensional photogrammetry and video analysis methods were utilized to conduct kinematic analysis on the technique employed by Ren Mengqian, an outstanding female pole vaulter in China, during the 2019 National Indoor Track and Field Championships finals from an energy transfer perspective. The findings indicate that during the energy acquisition stage, Ren Mengqian executed a reasonable jumping action with appropriate jumping angle and timing that met technical requirements. However, during the energy storage stage, her bow rod had suboptimal effects in her fourth trial jump while insufficient bending of the rod occurred in her fifth trial jump which affected pole energy storage. In terms of energy release stage, Ren Mengqian maximized elastic potential energy through stretching but required acceleration for maximum vertical speed.

Selective aortic arch perfusion: a first-in-human observational cadaveric study

BackgroundSelective aortic arch perfusion (SAAP) is a novel endovascular technique that combines thoracic aortic occlusion with extracorporeal perfusion of the brain and heart. SAAP may have a role in both haemorrhagic shock and in cardiac arrest due to coronary ischaemia. Despite promising animal studies, no data is available that describes SAAP in humans. The primary aim of this study was to assess the feasibility of selective aortic arch perfusion in humans. The secondary aim of the study was to assess the feasibility of achieving direct coronary artery access via the SAAP catheter as a potential conduit for salvage percutaneous coronary intervention.MethodsUsing perfused human cadavers, a prototype SAAP catheter was inserted into the descending aorta under fluoroscopic guidance via a standard femoral percutaneous access device. The catheter balloon was inflated and the aortic arch perfused with radio-opaque contrast. The coronary arteries were cannulated through the SAAP catheter.ResultsThe procedure was conducted four times. During the first two trials the SAAP catheter was passed rapidly and without incident to the intended descending aortic landing zone and aortic arch perfusion was successfully delivered via the device. The SAAP catheter balloon failed on the third trial. On the fourth trial the left coronary system was cannulated using a 5Fr coronary guiding catheter through the central SAAP catheter lumen.ConclusionsFor the first time using a perfused cadaveric model we have demonstrated that a SAAP catheter can be easily and safely inserted and SAAP can be achieved using conventional endovascular techniques. The SAAP catheter allowed successful access to the proximal aorta and permitted retrograde perfusion of the coronary and cerebral circulation.

Development of capsid- and genome-modified optimized AAVrh74 vectors for muscle gene therapy

The first generation of adeno-associated virus (AAV) vectors composed of the naturally occurring capsids and genomes, although effective in some instances, are unlikely to be optimal for gene therapy in humans. The use of the first generation of two different AAV serotype vectors (AAV9 and AAVrh74) in four separate clinical trials failed to be effective in patients with Duchenne muscular dystrophy, although some efficacy was observed in a subset of patients with AAVrh74 vectors leading to US Food and Drug Administration approval (Elevidys). In two trials with the first generation of AAV9 vectors, several serious adverse events were observed, including the death of a patient in one trial, and more recently, in the death of a second patient in an N-of-1 clinical trial. In a fourth trial with the first generation of AAVrh74 vectors, myositis and myocarditis were also observed. Here, we report that capsid- and genome-modified optimized AAVrh74 vectors are significantly more efficient in transducing primary human skeletal muscle cells invitro and in all major muscle tissues invivo following systemic administration in a murine model. The availability of optimized AAVrh74 vectors promises to be safe and effective in the potential gene therapy of muscle diseases in humans.

Valorization of spent Aureobasidium pullulans for the removal of toxic pollutant in wastewater treatment

Textile industries are growing rapidly due to increased demand for textile products worldwide. The discharge of textile effluent containing synthetic dyes, chlorides, pigments, aromatic compounds, and heavy metals contributes substantially to water pollution due to its toxicity and chemical composition. This work is focused on the potential usage of treated Aureobasidium pullulans biomass (TAPB) to remove the toxic chemical pollutant, Methylene Blue (MB), from an aqueous solution. Experimental results found that maximum MB removal of 76.5% was observed using TAPB dosage of 3 ​g/L, initial pH 8.0, temperature 30 ​°C, and initial MB concentration of 50 ​mg/L. The maximum biosorption capacity of TAPB was found to be 113.75 ​mg/g using the Langmuir non-linear approach. Successive biosorption and desorption experiments showed better regeneration capacity of TAPB until the fourth trial. These results demonstrated that maximum MB removal (%) could be possible with a small quantity of biomass, consequently offering a minimum size of the contactor and less capital cost requirement for biosorption. It also showed a greater regeneration capacity biosorbent for removing MB. Hence, the feedstock consumption for MB removal could be considerably decreased in large-scale processes.

Four-parameter analysis in modified Rotarod test for detecting minor motor deficits in mice

BackgroundThe Rotarod test with commercial apparatus is widely used to assess locomotor performance, balance and motor learning as well as the deficits resulting from diverse neurological disorders in laboratory rodents due to its simplicity and objectivity. Traditionally, the test ends when rodents drop from the accelerating, turning rod, and the only parameter used commonly is “latency to fall”. The values of individual animals can often vary greatly.ResultsIn the present study, we established a procedure for mice with 4 consecutive days of training with 4 trials per day and modified the testing procedure by placing the mice back on the rod repeatedly after each fall until the trial ends (5 min). Data from the fourth training day as baseline results showed that the second, third and fourth trial were more consistent than the first, probably due to habituation or learning. There was no difference between the second, third and fourth trial, two trials may be sufficient in testing. We also introduced 3 additional read-outs: Longest duration on the rod (s), Maximal distance covered (cm), and Number of falls to better evaluate the motor capacity over the 5 min of testing. We then used this 4-parameter analysis to capture the motor deficits of mice with mild to moderate traumatic brain injuries (by a weight dropping on the skull (Marmarou model)). We found that normalization of data to individual baseline performance was needed to reduce individual differences, and 4 trials were more sensitive than two to show motor deficits. The parameter of Maximal distance was the best in detecting statistically significant long-term motor deficits.ConclusionsThese results show that by making adjustments to the protocol and employing a more refined analysis, it is possible to expand a widely used routine behavioral test with additional accessible parameters that detect relevant deficits in a model of mild to moderate traumatic brain injury. The modified Rotarod test maybe a valuable tool for better preclinical evaluations of drugs and therapies.

Upper Limb Joint Angle Estimation Using Wearable IMUs and Personalized Calibration Algorithm

In physical therapy, exercises improve range of motion, muscle strength, and flexibility, where motion-tracking devices record motion data during exercises to improve treatment outcomes. Cameras and inertial measurement units (IMUs) are the basis of these devices. However, issues such as occlusion, privacy, and illumination can restrict vision-based systems. In these circumstances, IMUs may be employed to focus on a patient’s progress quantitatively during their rehabilitation. In this study, a 3D rigid body that can substitute a human arm was developed, and a two-stage algorithm was designed, implemented, and validated to estimate the elbow joint angle of that rigid body using three IMUs and incorporating the Madgwick filter to fuse multiple sensor data. Two electro-goniometers (EGs) were linked to the rigid body to verify the accuracy of the joint angle measuring algorithm. Additionally, the algorithm’s stability was confirmed even in the presence of external acceleration. Multiple trials using the proposed algorithm estimated the elbow joint angle of the rigid body with a maximum RMSE of 0.46°. Using the IMU manufacturer’s (WitMotion) algorithm (Kalman filter), the maximum RMSE was 1.97°. For the fourth trial, joint angles were also calculated with external acceleration, and the RMSE was 0.996°. In all cases, the joint angles were within therapeutic limits.

Honey bee death from aerosols inadvertently produced from propelled aerial dispersal of a solid ant bait.

Hydrogels are a new bait form, and multiple studies have found minimal potential or actual nontarget impacts associated with their use. However, in 2020, aerial applications of hydrogels containing fipronil unequivocally resulted in honey bee deaths. Here we detail four studies that then were conducted to determine how the bees were exposed to the active constituent and how to modify the aerial treatment protocols to eliminate the risk to bees. The first trial confirmed the existence of fipronil in aerosol form. The second trial quantified that in specific wind conditions the aerosols were falling to the ground at a maximum distance determined by an approximate 30° angle from the ground to the dispersal point, and that free-falling hydrogels either do not produce aerosols or, if so, at volumes too negligible to be collected or quantified. The third trial confirmed that even bee hives upwind and several hundreds of metres away from the area being baited can be contaminated by the aerosols. The fourth trial found no bee hive mortality as a result of either free-falling bait or moving bee hives 500 m beyond the treatment area. The aerosol issue is likely to occur with every motorized mechanism dispersing hydrogels. It is possible that the same issue happens with solid dry products if they produce a fine dust when propelled during dispersal. Further research into this issue is warranted. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Identifying the minimum concentrations of cell-free fetal DNA in maternal blood required for bovine fetal sexing using PCR

We evaluated the feasibility of cffDNA extraction from the maternal blood samples regarding the threshold concentrations required for fetal sexing in pregnant cattle by PCR. In four trials, we 1) compared the extraction efficiency of seven methods using freshly harvested plasma/blood of cows carrying male fetii (150–240 d gestation) bovine amelogenin (bAML) and Y-specific gene sequences, 2) identified the minimum amounts of spiked cffDNA needed for a PCR for fetal sexing, 3) determined the most optimal protocol among three commercial kits for cffDNA extraction from neat and spiked plasma samples (181–240 d gestation) for PCR detection of Y-specific sequence and 4) tested Y-specific sequence PCR on pregnant cows at different stages of gestation (60–150 versus 151–240 d pregnant). In these experiments, blood samples from unbred dairy heifers (Canadian Holstein, n = 10), pregnant dairy cows (Canadian Holstein, 60–240 d gestation, n = 25 with male fetii), and aborting beef cows (Angus cross, n = 5, 100–150 d pregnant) were used for DNA extraction, spiking, and PCR. Extracted DNA from the blood samples of unbred heifers (n = 5) and bull calves (n = 5) served as controls in all trials. In the first trial, DNeasy Blood and Tissue, Qiagen DSP Virus, and NucleoMag cfDNA isolation kits were relatively successful among seven methods to isolate cffDNA from freshly harvested maternal plasma/blood of pregnant cows. In trial 2, using serial dilutions of cffDNA from male fetii spiked in cow plasma samples, a positive and unambiguous detection by PCR targeting Y-specific sequence and bAML gene was observed when spiked cffDNA concentration in plasma was >31.3 pg/ml and >2 ng/ml, respectively. In the third trial, the DNeasy Blood and Tissue kit was most successful in extracting cffDNA spiked at the minimum concentrations in maternal plasma and subsequent PCR for Y-specific sequence. In our fourth trial, more cows in the second half (9/10) of gestation showed a positive Y-specific PCR outcome than those in the first half (3/9, Fischer's exact test; P < 0.05, 90%; CI: 55.5–99.75 vs 33%; CI: 7.5–70.1). In conclusion, we observed variability between different DNA extraction methodologies and stages of gestation results in the PCR for prenatal sexing. Thus, the current PCR methodologies are unreliable for detecting cffDNA in pregnant cows. Additionally, ≥10 (≥31.3 pg/ml of cffDNA) and ≥648 (≥2 ng/ml of cffDNA) copies of the whole fetal genome in bovine maternal plasma are needed for Y-specific PCR and bAML PCR, respectively.

Nonopioid drug combinations for cancer pain: a systematic review.

Pain is highly prevalent in patients with cancer-nearly 40% report moderate-severe pain, which is commonly treated with opioids. Increasing cancer survivorship, opioid epidemics in some regions of the world, and limited opioid access in other regions have focused attention on nonopioid treatments. Given the limitations of monotherapy, combining nonopioids-such as antiepileptics and antidepressants-have shown promise in noncancer pain. This review seeks to evaluate efficacy of nonopioid combinations for cancer-related pain. Systematic searches of PubMed, EMBASE, and Cochrane CENTRAL were conducted for double-blind, randomized, controlled trials comparing a nonopioid combination with at least one of its components and/or placebo. This search yielded 4 randomized controlled trials, published between 1998 and 2019 involving studies of (1) imipramine + diclofenac; (2) mitoxantrone + prednisone + clodronate; (3) pentoxifylline + tocopherol + clodronate; and (4) duloxetine + pregabalin + opioid. In the first 3 of these trials, trends favouring combination efficacy failed to reach statistical significance. However, in the fourth trial, duloxetine + pregabalin + opioid was superior to pregabalin + opioid. This review illustrates recognition for the need to evaluate nonopioid drug combinations in cancer pain, although few trials have been published to date. Given the growing practice of prescribing more than 1 nonopioid for cancer pain and the need to expand the evidence base for rational combination therapy, more high-quality trials in this area are needed.

Sudden Changes in Water Hardness Do Not Impact Short-Term Rainbow Trout Survival

Fish transferred from hard water to soft water, as can occur during the stocking of hatchery-reared fish into natural environments, experience many physiological stressors that can cause mortality. This study consisted of four trials examining the effects of direct transfer from hard (345 mg/L CaCO3) to soft water on mortality and glucose stress response of two different sizes and strains of rainbow trout Oncorhynchus mykiss. The first trial subjected 90 g Shasta strain rainbow trout to a direct transfer to soft water (70 or 160 mg/L as CaCO3). The second trial used the same strain and size trout, with transfer to lower hardness values of either 0 or 35 mg/L. The third and fourth trials used 3 to 5 g Arlee strain rainbow trout. The third trial transferred the fish from 345 mg/L hardness water to water at a hardness of either 0 or 35 mg/L. The fourth trial added a secondary temperature stressor of 20 °C (versus the experimental standard of 11 °C) in combination with a hardness level of 0 mg/L. In every trial, survival was not significantly different among all treatments. Sudden and extreme changes in water hardness, even in combination with increased water temperature, did not cause trout mortality. There was also no significant difference in blood glucose over time among any of the treatments in the first three trials. In the fourth trial, glucose values did significantly vary among the treatments at 48 and 168 h after the start of the trial. However, all glucose values were relatively close to the basal level. These results indicate that changes in water hardness likely do not impact the survival of rainbow trout, negating the need for tempering or acclimation.

Exercise interventions to reduce anxiety in mid-life and late-life anxiety disorders and subthreshold anxiety disorder: a systematic review.

Background:Anxiety disorders are highly prevalent and cause significant distress, disability, and cost. Medication adverse effects and interactions increase in mid-life and late-life, highlighting the need for effective non-pharmacological interventions.Objectives:We aimed to evaluate the extent of evidence supporting exercise interventions for anxiety and subthreshold anxiety disorders in mid-life and late-life.Design:Systematic review.Data Sources and Methods:We searched MEDLINE, PsycINFO, Embase, Emcare, Ovid Nursing, CINAHL Plus, Cochrane Library, Health Collection, Humanities & Social Sciences Collection, and https://clinicaltrials.gov databases for trials published January 1994–May 2019. Randomised controlled trials of exercise interventions involving aerobic exercise or resistance training for adults aged 40 years and above with anxiety or subthreshold anxiety disorders in residential or health settings were identified. The primary outcome was change in anxiety. We excluded trials including participants aged below 40 years, participants with diagnosis of separation anxiety, selective mutism, obsessive-compulsive disorder, acute stress disorder and post-traumatic stress disorder, and head-to-head comparisons of interventions. Trial quality was assessed using the Cochrane Risk of Bias Tool and evidence synthesised in narrative form.Results:Four trials totalling 132 participants met inclusion criteria, although some had methodological limitations. Interventions included a home-based resistance training intervention, supervised group-based aerobic intervention, Tai Chi intervention, and supervised group-based aerobic and strength intervention. Three trials included late-life participants and the fourth mid-life. Three trials demonstrated greater reductions in anxiety in the intervention group compared with control. The fourth trial showed pre–post reductions in anxiety in both groups, with between-group difference not reaching statistical significance.Conclusion:There is limited supportive evidence suggesting that exercise interventions have potential to be effective, feasible and safe non-pharmacological interventions for anxiety and subthreshold anxiety disorders in mid-life and late-life. The heterogeneity, limited number and high risk of bias of some trials meant that we were not able to conduct a meta-analysis. Tailoring of interventions may improve uptake and reduce dropout. The paucity of research in this area with only four included trials demonstrates the urgent need for future and larger trials to provide proof of concept, data about effective types and doses of exercise interventions, and guidance to community, clinical, and public health services.

Nursery Management of Two Major Below-Ground Feeding Plant Pests: Root Mealybug,Rhizoecus sp. and Rice Root Aphid,Rhopalosiphum rufiabdominalis(Sasaki) (Hemiptera: Pseudococcidae and Aphididae)

AbstractRoot mealybug (Rhizoecus sp.) and rice root aphid (Rhopalosiphum rufibdominalis) are below-ground feeding insects that are difficult to control and have become major pests as production of their host plants has grown. Field trials were designed to investigate the impact new insecticides and biopesticides have on root mealybugs and rice root aphids. In our first three trials, we investigated the effects of biopesticides, entomopathogenic nematodes or fungi on reflexed stonecrop (Sedum rupestre) and stonecrop (S. montanum) against root mealybug. We found that flupyradifurone (Altus), flonicamid (Aria), chlorantraniliprole (Acelepryn), pymetrozine (Endeavor), Beauveria bassiana (Mycotrol), Chromobacterium subtsugae (Grandevo), Burkholderia spp. strain A396 (Venerate), cyantraniliprole (Mainspring) and Steinernema carpocapsae (Millenium) significantly reduced root mealybug populations compared to nontreated controls when applied as drenches in a curative manner. In our fourth trial, we evaluated biopesticides and Beauveria bassiana, on rice root aphid feeding on common rush (Juncus effusus) roots. Results showed pymetrozine significantly reduced populations as early as 14 days after treatment and continued to reduce their population throughout the remainder of the trial. However, chlorantraniliprole, cyantraniliprole, Beauveria bassiana, M-306 and MBI-203 did not significantly reduce rice root aphid populations until 28 days after initial application. Predator activity on root balls of Juncus effusus plants was also noted during the trials and may provide an integrated pest management (IPM) approach in controlling populations.Index words: reflexed stonecrop, Sedum rupestre L, stonecrop, Sedum montanum Song. &amp; Perr, common rush, Juncus effuses L, Beauveria bassiana, Mycotrol, Steinernema carpocapsae, Millenium, reduced-risk pesticides, Chromobacterium subtsugae (Grandevo), flupyradifurone, Altus, flonicamid, Aria, chlorantraniliprole, Acelepryn, pymetrozine, Endeavor, Burkholderia spp. strain A396, Venerate, cyantraniliprole, Mainspring, M-306, MBI-203.Chemicals used in this study: flupyradifurone (Altus); flonicamid (Aria); chlorantraniliprole (Acelepryn); cyantraniliprole (Mainspring); pyrometrozine (Endeavor); Burkholderia spp. strain 396 (Venerate); Chromobacterium subtsugae (Grandevo); Beauveria bassiana (Mycotrol); AMBI-203 WDG – 30% Chromobacterium subtsugae strain PRAA4-1T cells and spent fermentation media. EPA registration number 84059-27; MBI-206 EP – 94.46% Heat-killed Burkholderia spp. strain A396 cells and spent fermentation media. EPA registration number 84059-14; MBI-203 SC2 – 98% Chromobacterium subtsugae strain PRAA4-1T cells and spent fermentation media. Experimental; MBI-306 SC1 - 94.46% non-viable Burkholderia spp. strain A396 cells and spent fermentation media. Experimental.Species used in this study: Root mealybug, Rhizoecus sp; Rice root aphid, Rhopalosiphum rufiabdominalis (Sasaki); reflexed stonecrop, Sedum rupestre; stonecrop, Sedum montanum; common rush, Juncus effusus.

Anterior thalamic NMDA-induced damage impairs extrapolation relying on serial stimulus patterns, in rats

Extrapolation of serial stimulus patterns seems to depend upon identification and application of patterns relating sequences of stimuli stored in memory, thus allowing prediction of pending events never experienced before. There have been proposals that such a “generator of predictions system” would include the subiculum, mammillary bodies, anteroventral thalamus and cingulate cortex (e.g., Gray, 1982). The anteroventral thalamus (AVT) seems to be in a strategic position, both hodologically and experimentally, to allow testing of this hypothesis. This study investigated the effect of NMDA-induced damage to the anteroventral thalamus [part of the anterodorsal (AD) thalamus was also damaged in some animals], following stereotaxic minute topic microinjections, on the ability of male Wistar rats to extrapolate relying on serial stimulus patterns. Corresponding sham-operated controls received phosphate-saline buffer microinjections at the same stereotaxic coordinates. The subjects were trained to run through a straight alleyway along 31 sessions, one session per day, to get rewarded. Each session included four successive trials. Subjects exposed to the monotonic serial pattern received 14, 7, 3, 1 sunflower seeds along trials. Subjects exposed to the non-monotonic serial pattern received 14, 3, 7, 1 sunflower seeds. On the 32nd testing session, a fifth trial, never experienced before, was included immediately after the fourth trial. Sham-operated control subjects exposed to the monotonic serial pattern were expected to exhibit longer running times, since the content of their prediction in the fifth trial should be “less than 1 sunflower seeds”. In contrast, control subjects exposed to the non-monotonic serial pattern were expected to exhibit shorter running times, since the content of their prediction would be “more than 1 sunflower seeds”. Confirming these predictions, control subjects exposed to the monotonic serial pattern exhibited longer running times as compared to both, their own running times in previous trials within the same session and control subjects exposed to the non-monotonic schedule, thus indicating the occurrence of extrapolation. In contrast, AVT/AD lesioned subjects exposed to the monotonic schedule did not exhibit this increase in running times on the fifth trial, indicating lack of extrapolation. These results indicate that extrapolation relying on serial stimulus patterns is disrupted following extensive NMDA-induced damage to AVT and part of the AD. This represents the first consistent demonstration that the anterior thalamic nuclei are required for extrapolation of serial stimulus patterns and generation of predictions.