Quarter Dose Research Articles

Efficacy of Every Four Monthly and Quarterly Dosing of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration

Faricimab neutralizes angiopoietin-2 and vascular endothelial growth factor A via both simultaneous and independent binding. To evaluate extended dosing with faricimab, the first bispecific antibody designed for intraocular use, in patients with neovascular age-related macular degeneration. This phase 2 randomized clinical trial was a 52-week multicenter, active comparator-controlled, parallel-group study. Study participants were enrolled in 25 sites in the US from January and March 2017 with treatment-naive choroidal neovascularization secondary to neovascular age-related macular degeneration and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score of 73 (approximate Snellen equivalent, 20/40) to 24 (approximate Snellen equivalent, 20/320). Analysis began January 2017 and ended March 2018. Participants were randomized 1:2:2 to receive intravitreal ranibizumab, 0.5 mg, every 4 weeks or faricimab, 6.0 mg, every 12 or 16 weeks. Participants in the faricimab arms initially received 4 monthly injections of faricimab. No rescue injections were allowed. Participants randomized to dosing every 16 weeks were assessed for disease activity at week 24 using prespecified criteria. Those with no active disease continued dosing every 16 weeks through trial end; participants with disease activity continued received dosing every 12 weeks. Mean change in BCVA from baseline at week 40. Of 76 participants enrolled (mean [SD] age, 78.5 [8.5] years; age range, 56-94 years; 41 women [58%]; 69 white [97%]), 16 (21.0%) were randomized to ranibizumab every 4 weeks, 29 (38.2%) to faricimab every 12 weeks, and 31 (40.8%) to faricimab every 16 weeks. At week 24, 12 weeks after their last initiation injection, 65% (36 of 55) of all faricimab-treated participants had no disease activity. At week 40, adjusted mean BCVA gains from baseline (Early Treatment Diabetic Retinopathy Study letters) were +11.4 (80% CI, 7.8-15.0), +9.3 (80% CI, 6.4-12.3), and +12.5 (80% CI, 9.9-15.1) for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively. Participants received a mean (SD) total of 12.9 (0.25), 6.7 (0.91), and 6.2 (0.93) injections, for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively, through week 52. The secondary BCVA and anatomical imaging end points supported the primary end point and were comparable with ranibizumab every 4 weeks. No new or unexpected safety signals were identified. At week 52, faricimab dosing every 16 weeks and every 12 weeks resulted in maintenance of initial vision and anatomic improvements comparable with monthly ranibizumab. These results suggest a role for simultaneous neutralization of angiopoietin-2 and vascular endothelial growth factor A in providing sustained efficacy through extended durability, warranting further investigation. ClinicalTrials.gov Identifier: NCT03038880.

Effects of a Gonadotropin‐Releasing Hormone IIa 5/20‐μg/kg Dose versus a 20/80‐μg/kg Dose on Channel Catfish Ovulation

AbstractThe production of (male Blue Catfish Ictalurus furcatus × female Channel Catfish Ictalurus punctatus) F1 hybrids by U.S. catfish farmers has increased dramatically during the last 15 years. However, hybrid catfish production requires hormone‐induced ovulation of female Channel Catfish and remains an inefficient process. Previously, we demonstrated that GnRH IIa given as a two‐dose injection (priming/induction) of 20/80 μg/kg of female body weight resulted in superior ovulation rates for Channel Catfish compared with salmon GnRH IIIa and mammalian LHRHa, which are products that are currently used at commercial catfish hatcheries. The objective of the current study was to determine whether GnRH IIa given at a quarter dose (5/20 μg/kg) would achieve results similar to those that were obtained with the full dose (20/80 μg/kg) and whether the response varied over the spawning season. Trials were conducted at three timepoints during the 2017 spawning season: early (May 1), middle (May 15), or late (June 5). At each timepoint, 20 females received an intraperitoneal injection with a full dose of GnRH IIa and 20 females received an injection with a quarter dose of GnRH IIa. Data were collected for female weight, latency, incidence of ovulation, and stripped eggs weight (g) per kilogram of female body weight. The data indicated that the quarter dose of GnRH IIa (5/20 μg/kg of female body weight) achieved results that were similar to those that were obtained with the full dose of 20/80 μg/kg.

RETINAL LEAKAGE INDEX DYNAMICS ON ULTRA-WIDEFIELD FLUORESCEIN ANGIOGRAPHY IN EYES TREATED WITH INTRAVITREAL AFLIBERCEPT FOR PROLIFERATIVE DIABETIC RETINOPATHY IN THE RECOVERY STUDY.

Characterization of leakage indices on ultra-widefield fluorescein angiography in proliferative diabetic retinopathy treated with intravitreal aflibercept. Prospective study enrolling subjects for treatment of proliferative diabetic retinopathy randomized 1:1 to receive 2-mg intravitreal aflibercept every 4 weeks (2q4) or every 12 weeks (2q12). Ultra-widefield fluorescein angiography images obtained at baseline, 24, and 48 weeks were analyzed using a semiautomated leakage segmentation platform. Panretinal and zonal leakage indices were calculated. Forty eyes of 40 subjects were included, and mean age was 48 ± 12.1 years. Mean number of injections was 11 ± 1.7 in the 2q4 arm and 4 ± 0.4 in the 2q12 arm. Median baseline leakage index in the 2q4 and 2q12 groups was 5.1% and 4.3%, respectively (P = 0.28). At 24 and 48 weeks, the 2q4 group significantly improved to 1.1% (-79%, P < 0.0001). At Week 24, the 2q12 group demonstrated nonsignificant improvement (3.4%; -21%, P = 0.47); by Week 48, improvement was significant (1.4%; -68%, P = 0.02). The 2q4 group resulted in lower leakage index compared with the 2q12 group at 24 weeks (1.1% vs. 3.4%, respectively; P = 0.008), but by 48 weeks, leakage index was similar between both groups (1.1% vs. 1.4%, respectively; P = 0.34). Proliferative diabetic retinopathy treated with intravitreal aflibercept demonstrated significant leakage index reductions at 1 year. Monthly dosing provided more rapid reduction in leakage index compared with quarterly dosing. RECOVERY study (NCT02863354); https://clinicaltrials.gov/ct2/show/NCT02863354.

The influence of pesticides repellency used in oilseed rape (Brassica napus subsp. napus) on the preference by bees (Apis mellifera L.)

The occurrence of honey bees was observed in fields of oilseed rape (Brassica napus subsp. napus) during the flowering period. The investigation revealed that the farmer was using different pesticides against pests and diseases during that time. Experiments using the feeding stations (Free-Choice Trials) method with honey solutions containing pesticides revealed that the repellency effect of pesticide formulations is different with some even attractive to honey bees. Experiments were held outdoors close to bee colonies and indoors in a fly-through hall in controlled conditions and commercial pesticides were used. The highest repellency in outdoors/indoors experiments was observed using the solution with formulations of pesticide Horizon 250 EW (a. c. tebuconazole) – 96.5%/99% and Nurelle D (a. c. chlorpyriphos-cypermethrin) 88%/97%, and the lowest repellency was observed for solution with formulations of Plenum (a. c. pymetrozine) – 19.2%/27.8%, Mospilan 20 SP (a. c. acetamiprid) – 20%/23.8%. The most repellent pesticides were diluted to half and a quarter of the recommended dose. The reducing of the active ingredient concentration improved attractiveness to honey bees, especially with Trebon OSR (74.3% for half dose and 55.8 for quarter dose) and Nurelle D (77.8% for half dose and 66.7 for quarter dose). However, a quarter dose of Horizon 250 EW did not show any substantial change in repellency (90.7%). Further investigations in field conditions will be done.

Lethal and Histological Effects of Neonicotinoids Insecticides on Apis mellifera (Hymenoptera, Apiadae)

Using of Neonicotinoids insecticides affect honeybees that visit field and horticultural crops for collecting nectar and pollen. Therefore, this investigation aimed to study the effect of three neonicotinoids insecticides (Imidacloprid, Acetamiprid and Dinotefuran,) with three (recommended, half, and quarter) doses on mortality rate of adult bees, also their effect on midgut tissues under laboratory conditions. The obtained results showed that a highly mortality% was recorded in Dinotefuran 100% after 48hr, while Acetamiprid revealed the lowest mortality% as 56, 51 and 33% with recommended, half and quarter dose, respectively. Imidacloprid recorded 81, 79 and 74% mortality for recommended, half and quarter dose, respectively. On the other hand, there was mild vacuolar degeneration with nucleus pyknosis in some cells in the lining mucosal epithelium of minimum concentration half recommended dose of Imidacloprid. Also, there was moderate proliferation of cells lining midgut with increasing number of goblet cells of the quarter recommended dose of Acetamiprid.It could be concluded that Dinotefuran is very dangerous and lethal on bees.

Quarterly Anti-Vascular Endothelial Growth Factor Dosing for Neovascular Age-Related Macular Degeneration: Real-World Clinical Outcomes.

Characterize eyes managed with quarterly intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration (nAMD). Treatment-naïve nAMD eyes managed predominately using a treat-and-extend approach that received five or more consecutive quarterly injections from 2005 to 2017. One hundred fifty eyes were retrospectively identified. During quarterly dosing, a mean of 9.8 injections were given over a mean of 29 months. Ninety-one eyes (61%) had no exudative disease recurrence during quarterly dosing. Thirty-three eyes (22%) experienced exudative activity recurrence, with a mean cumulative yearly recurrence rate of 12% and a mean 6-letter loss of visual acuity (VA). Twenty-four eyes (16%) stopped quarterly treatments; nine (38%) of these subsequently experienced exudative activity recurrence with a mean 8-letter VA loss. In this real-world analysis of nAMD managed with quarterly dosing over a mean of more than 2 years' follow-up, 22% experienced disease recurrence during quarterly dosing, and 38% of eyes that stopped quarterly dosing experienced subsequent exudative disease recurrence. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e250-e256.].

Fremanezumab in the treatment of migraines: evidence to date.

Calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology, and CGRP monoclonal antibodies including fremanezumab may be a safe effective preventive therapy. Phase IIb studies in episodic migraine (EM) and chronic migraine (CM) demonstrated efficacy at both the monthly 225 mg and quarterly 675 mg doses. The Phase III trials for EM and CM both showed a reduction in the primary endpoint of monthly migraine days (MMD). In the EM trial, the baseline MMD of 8.9 days was reduced to 5.3 at 12 weeks and to 4.0 days in the 6-month open-label extension (OLE) for monthly dosing. In the quarterly dosing, the baseline was 9.2 days reduced to 5.3 at 12 weeks and to 4.2 days in the OLE. In the CM data for monthly dosing, the baseline was 16.2 days decreased to 11.4 at 12 weeks then to 8.3 in the OLE. In the CM quarterly dosing, the baseline of 16.4 days was reduced to 11.9 at 12 weeks and 9.9 days in the OLE. Randomized controlled trials of fremanezumab in both episodic cluster and post-traumatic headache are underway, but the trial for chronic cluster headache was stopped for futility. The most common adverse events are injection site pain (24% vs 22% for placebo), induration (17% vs 13% for placebo), and erythema (16% vs 12% for placebo). Severe adverse events were reported in 3.9% of the fremanezumab vs 3.7% of the placebo. No changes in vitals or ECG were reported. The long-term effects are not known, but the American Headache Society recommends that CGRP monoclonal antibodies be considered in EM or CM depending on previous medication trials and headache disability/frequency. Further, post-market studies are required, but for EM and CM fremanezumab is a new option for migraine preventive treatment.

Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy: Outcomes from the Randomized RECOVERY Trial

Evaluate the impact of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) on retinal nonperfusion (RNP) in eyes with proliferative diabetic retinopathy (PDR). Prospective, randomized clinical trial. Eyes with treatment-naïve PDR and extensive RNP without diabetic macular edema. Patients were randomized 1:1 to intravitreal 2 mg aflibercept every 4 weeks (monthly) or every 12 weeks (quarterly). The primary outcome measure was change in total RNP area (in square millimeters) from baseline to year 1. Secondary outcomes included ischemic index (ISI), diabetic retinopathy severity scale (DRSS) scores, visual acuity, central retinal thickness, and adverse events. The mean and 95% confidence interval were calculated for each outcome. Through 1 year, the monthly (n= 20) and quarterly (n= 20) cohorts received 11.0 and 3.95 mean aflibercept injections, and DRSS scores improved 2 steps or more in 74% and 67% of patients, respectively. Among all patients through 1 year, mean total area of RNP increased from 235 mm2 to 266 mm2 (P= 0.18) and ISI increased from 25.8% to 31.9% (P= 0.004). Retinal nonperfusion outcomes favored monthly dosing. Mean total RNP increased from 207 mm2 at baseline to 268 mm2 (P= 0.01) at 1 year in the quarterly cohort and remained stable at 264 mm2 at baseline and 1 year (P= 0.70) in the monthly cohort (P= 0.05, monthly vs. quarterly cohorts). Although many eyes demonstrated increased areas of RNP longitudinally (n= 24 [66.7%]), this was more common with quarterly dosing (n= 14 [77.8%]), and a proportion of eyes (n= 12 [33.3%]) demonstrated localized areas of apparent reperfusion of nonperfused retina, more commonly in the monthly cohort (n= 8 [44.4%]). Widespread evidence of retinal reperfusion with aflibercept dosing of PDR eyes with extensive RNP was not identified, and therefore the primary outcome of the current study was not met. Nevertheless, zones of apparent reperfusion were detected in some patients, and a dose response was identified with a reduction of RNP progression with monthly compared to quarterly dosing.

Optimization of Xylazine-Ketamine Anesthetic Dose in Mice with Chronic Liver Injury

Objective:The aim of the present study was to find the safest and appropriate intraperitoneal injection dose of Ketamine-Xylazine cocktail for short to the medium-duration surgical procedure (ultrasound-guided liver biopsy) in rats suffering chronic liver injury. Methods:Four anesthetic doses of Ketamine-Xylazine combination were compared for their safety and efficacy (death rate and surgical tolerance), using observations and reflex tests. Anesthesia evaluated during ultrasound-guided liver biopsy procedure. The reactions of physiological parameters to surgical stimuli were used to determine anesthesia depth and were correlated with reflex test results. Results: Full dose of Ketamine-Xylazine (87 mg/ kg- 13 mg/ kg) rapidly induced a deep state of anesthesia that lasted for about 70 minutes followed by complete cessation of respiration and death. Three-quarters dose of the cocktail also, rapidly induced a deep state of anesthesia that lasted 45 minutes. Anesthesia was adequate to perform the procedure. Recovery was long. No postoperative complications detected. Half dose of the Ketamine-Xylazine cocktail was short acting. Very good analgesia and muscle relaxation were recorded. Anesthesia lasted for about 30 minutes that was adequate for performing the procedure. Physiological parameters decreased followed by rapid stabilization. Smooth recovery noted. No postoperative complication recorded. Quarter dose produced a state of sedation. Analgesia and muscle relaxation were poor. Animals showed pain during manipulation. The procedure could not be achieved. Conclusions:The optimal intraperitoneal dose of Ketamine-Xylazine cocktail for balanced anesthesia in lab rats suffering chronic liver injury is (43.5 mg/kg and 6.5 mg/kg) respectively.

Physician and patient preferences for dosing options in migraine prevention

BackgroundAdherence to a therapy, though a key factor for successful treatment, is low among patients with chronic conditions such as migraine. Dose frequency plays a major role in adherence. This study evaluated the impact of having flexible dosing options on acceptance of and adherence to a new migraine preventive therapy class among adults with migraine.MethodsIn this observational study, two 20-min online surveys were completed: one by physicians currently treating adult patients with migraine and the other by adults with migraine. Both surveys presented the participants with three scenarios: 1) only monthly, 2) only quarterly, and 3) both dosing options of the new medication are available. Physicians estimated the proportion of their migraine patients who would receive the new medication in each scenario. Patients were asked about their dosing preference when either or both options are available. Respondents were asked to rate the likelihood of their acceptance of and adherence to the therapy.Results400 physicians and 417 US adults with migraine completed the surveys. The availability of both dosing options yielded a significant increase in the proportion of patients expected to receive the new medication. The overall proportion of patients favoring monthly dosing (35%) was similar to the proportion favoring quarterly dosing (40%). Among those who preferred monthly dosing (n = 147), a greater proportion indicated they are more likely to fill the prescription (77% vs 56%, P < 0.05) and remain adherent (80% vs 57%, P < 0.05) when only monthly is available versus when only quarterly is available. Similarly, among those who preferred quarterly dosing (n = 166), a greater proportion indicated they are likely to fill (63% vs 55%, P < 0.05) and remain adherent (62% vs 54%, P < 0.05) when only quarterly is available compared with when only monthly is available.ConclusionsPhysicians anticipated that the proportion of patients to receive the new medication would increase when both dosing options are available. Patients stated that they are more likely to fill the prescription and adhere to the new therapy when their preferred dosing regimen is available.

Localization of liver lesions in abdominal CT imaging: I. Correlation of human observer performance between anatomical and uniform backgrounds**Selected sections presented during oral presentation at 2017 RSNA Annual Meeting.

The purpose of this study was to determine the correlation between human observer performance for localization of small low contrast lesions within uniform water background versus an anatomical liver background, under the conditions of varying dose, lesion size, and reconstruction algorithm.Liver lesions (5 mm, 7 mm, and 9 mm, contrast: −21 HU) were digitally inserted into CT projection data of ten normal patients in vessel-free liver regions. Noise was inserted into the projection data to create three image sets: full dose and simulated half and quarter doses. Images were reconstructed with a standard filtered back projection (FBP) and an iterative reconstruction (IR) algorithm. Lesion and noise insertion procedures were repeated with water phantom data. Two-dimensional regions of interest (66 lesion-present, 34 lesion-absent) were selected, randomized, and independently reviewed by three medical physicists to identify the most likely location of the lesion and provide a confidence score. Locations and confidence scores were assessed using the area under the localization receiver operating characteristic curve (AzLROC). We examined the correlation between human performance for the liver and uniform water backgrounds as dose, lesion size, and reconstruction algorithm varied.As lesion size or dose increased, reader localization performance improved. For full dose IR images, the AzLROC for 5, 7, and 9 mm lesions were 0.53, 0.91, and 0.97 (liver) and 0.51, 0.96, and 0.99 (uniform water), respectively. Similar trends were seen with other parameters. Performance values for liver and uniform backgrounds were highly correlated for both reconstruction algorithms, with a Spearman correlation of ρ = 0.97, and an average difference in AzLROC of 0.05 ± 0.04.For the task of localizing low contrast liver lesions, human observer performance was highly correlated between anatomical and uniform backgrounds, suggesting that lesion localization studies emulating a clinical test of liver lesion detection can be performed using a uniform background.

Localization of liver lesions in abdominal CT imaging: II. Mathematical model observer performance correlates with human observer performance for localization of liver lesions in abdominal CT imaging**Selected sections presented during digital poster presentation at 2017 RSNA Annual Meeting.

Determination of the effect of protocol modifications on diagnostic performance in CT with human observers is extremely time-consuming, limiting the applicability of such methods in routine clinical practice. In this work, we sought to determine whether a channelized Hotelling observer (CHO) could predict human observer performance for the task of liver lesion localization as background, reconstruction algorithm, dose, and lesion size were varied.Liver lesions (5 mm, 7 mm, and 9 mm) were digitally inserted into the CT projection data of patients with normal livers and water phantoms. The projection data were reconstructed with filtered back projection (FBP) and iterative reconstruction (IR) algorithms for three dose levels: full dose (liver CTDIvol = 10.5 ± 8.5 mGy, water phantom CTDIvol = 9.6 ± 0.1 mGy) and simulated half and quarter doses. For each of 36 datasets (3 dose levels × 2 reconstruction algorithms × 2 backgrounds × 3 sizes), 66 signal-present and 34 signal-absent 2D images were extracted from the reconstructed volumes. Three medical physicists independently reviewed each dataset and noted the lesion location and a confidence score for each image. A CHO with Gabor channels was calculated to estimate the performance for each of the 36 localization tasks. The CHO performances, quantified using localization receiver operating characteristic (LROC) analysis, were compared to the human observer performances.Performance values between human and model observers were highly correlated for equivalent parameters (same lesion size, dose, background, and reconstruction), with a Spearman’s correlation coefficient of 0.93 (95% CI: 0.82–0.98). CHO performance values for the uniform background were strongly correlated (ρ = 0.94, CI: 0.80–1.0) with the human observer performance values for the liver background.Performance values between human observers and CHO were highly correlated as dose, reconstruction type and object size were varied for the task of localization of patient liver lesions in both uniform and liver backgrounds.

The Impact of Offering Monthly and Quarterly Dosing Options for a New Class of Migraine Preventive Therapy on Likelihood of Acceptance and Adherence in Adults With Migraine (P3.10-013)

The Impact of Offering Monthly and Quarterly Dosing Options for a New Class of Migraine Preventive Therapy on Likelihood of Acceptance and Adherence in Adults With Migraine (P3.10-013)

Role of paliperidone palmitate 3-monthly in the management of schizophrenia: insights from clinical practice.

Schizophrenia is a complex, chronic psychiatric disorder associated with reduced quality of life and shortened life span. The majority of patients with schizophrenia will relapse within 1 year following an acute episode. The ultimate goals of treatment are to improve functional capabilities, minimize residual symptoms during periods of remission, and decrease relapse frequency and duration, as each relapse brings with it the possibility of a worsening prognosis. Maintaining therapeutic continuity is essential for long-term, positive patient outcomes in schizophrenia. Medication nonadherence and symptomatic relapses magnify the disease burden associated with this disorder. Medication adherence in chronic disease states generally improves with a decrease in dosing frequency. Long-acting injectable (LAI) antipsychotics were developed to improve patient outcomes secondarily to improving medication adherence. Paliperidone palmitate 3-monthly injection (PP3M) is the only LAI available with a quarterly dosing interval. PP3M has been US Food and Drug Administration-approved for use in the long-term maintenance treatment of schizophrenia in patients already controlled on once-monthly PP LAI (paliperidone palmitate once-monthly injection [PP1M]) for a minimum of 4 months. As current evidence supports the efficacy and tolerability of PP3M compared to PP1M and placebo, PP3M appears to be a viable treatment option for patients previously maintained on PP1M. However, to truly establish the place of PP3M in therapy relative to other oral antipsychotics and LAIs, more research is needed. This narrative review aims briefly to describe the pharmacotherapeutic characteristics of PP3M and summarize current literature pertaining to the use of PP3M in the management of schizophrenia.

MDCT-based Finite Element Analysis of Vertebral Fracture Risk: What Dose is Needed?

The aim of this study was to compare vertebral failure loads, predicted from finite element (FE) analysis of patients with and without osteoporotic vertebral fractures (OVF) at virtually reduced dose levels, compared to standard-dose exposure from multidetector computed tomography (MDCT) imaging and evaluate whether ultra-low dose derived FE analysis can still differentiate patient groups. An institutional review board (IRB) approval was obtained for this retrospective study. A total of 16patients were evaluated at standard-dose MDCT; eight with and eight without OVF. Images were reconstructed at virtually reduced dose levels (i. e. half, quarter and tenth of the standard dose). Failure load was determined at L1-3 from FE analysis and compared between standard, half, quarter, and tenth doses and used to differentiate between fracture and control groups. Failure load derived at standard dose (3254 ± 909 N and 3794 ± 984 N) did not significantly differ from half (3390 ± 890 N and 3860 ± 1063 N) and quarter dose (3375 ± 915 N and 3925 ± 990 N) but was significantly higher for one tenth dose (4513 ± 1762 N and 4766 ± 1628 N) for fracture and control groups, respectively. Failure load differed significantly between the two groups at standard, half and quarter doses, but not at tenth dose. Receiver operating characteristic (ROC) curve analysis also demonstrated that standard, half, and quarter doses can significantly differentiate the fracture from the control group. The use of MDCT enables adose reduction of at least 75% compared to standard-dose for an adequate prediction of vertebral failure load based on non-invasive FE analysis.

Improvement of safflower oil quality for biodiesel production by integrated application of PGPR under reduced amount of NP fertilizers

Safflower is an important industrial oil seed and bioenergy crop in semi-arid subtropical regions due to its potential to grow on marginal land and having good percentage of seed oil contents which is an important parameter for biofuel production. However, it is an ignored crop in Pakistan. In order to improve the crop productivity and reduce the use of agrochemicals for sustainable biodiesel feedstock production, an experiment was conducted for two years to improve the fatty acid composition and oil quality of Carthamus tinctorius L. (safflower) by the inoculation of Azospirillum and Azotobacter alone as well as in combined application with nitrogen and phosphate (NP) fertilizers on cultivars Thori and Saif-32 under field conditions. Separation and quantification of fatty acids were done on precise comprehensive two-dimensional gas chromatography (GC×GC). The results showed that fatty acid profile specifically monounsaturated fatty acids i-e oleic acid (C18:1) was significantly improved by Azospirillum supplemented with the quarter dose of NP fertilizers (SPQ) with concomitant decrease in polyunsaturated fatty acids by the respective treatment. Oil quality attributes such as acid value, saponification number, iodine value, refractive index and free fatty acid contents were reduced by the application of Azotobacter and Azospirillum in combination with half and quarter doses of NP fertilizers treatments (BTH, SPH, BTQ and SPQ). The reduction in these variables is positively linked with improved biodiesel yield and quality. It can be concluded that application of Azospirillum and Azotobacter not only reduced the use of NP fertilizers up to 50%–75% but also improved the oil quality in order to obtain environment friendly, sustainable and green fuel.

INTRAMUSCULAR ADMINISTRATION OF KETAMINE-MEDETOMIDINE ASSURES STABLE ANAESTHESIA NEEDED FOR LONG-TERM SURGERY IN THE ARGENTINE TEGUSALVATOR MERIANAE

To define a protocol of anesthesia for long-duration invasive surgery in a lizard, eight young adult Argentine tegus ( Salvator merianae) of mean body weight 3.0 kg (interquartile range [IQR] 3.40-2.65) were anesthetized with a mixture of ketamine (K) and medetomidine (M) at 19°C, injected intramuscularly and equally distributed in the four limbs. As the experimental surgery procedure required a prolonged deep anesthesia with a good myorelaxation (between 16 and 21 hr), reinjections were required and reflexes were checked during surgery. Times for anesthetic induction, anesthetic reinjection, and recovery periods were recorded for five different combinations of ketamine-medetomidine: 1) 66 mg/kg K + 100 μg/kg M; 2) 80 mg/kg K + 100 μg/kg M; 3) 100 mg/kg K + 130 μg/kg M; 4) 125 mg/kg K + 200 μg/kg M; and 5) 150 mg/kg K + 200 μg/kg M. The effect on the recovery speed of the postoperative atipamezole injection was also evaluated. The median induction time was 30 (IQR 35-27.5) min with no statistical difference between all the concentrations tested. The first reinjection of half a dose was administered after a mean of 5 hr (5.64 hr, IQR 5.95-4.84) as were the subsequent reinjections of a quarter dose (3.99 hr, IQR 5.98-3.23). Intramuscular administration of the ketamine-medetomidine combination is a simple, rapid, and efficient anesthesia for long-term surgery (>12 hr). A mix of 100 mg/kg ketamine and 200 μg/kg medetomidine, with reinjections every 4 hr of half a dose of the previous injection can maintain a good quality of anesthesia for at least 16 hr. The injection of atipamezole after the surgery reverses the effects of medetomidine and permits a reduction of the recovery period.

Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine

Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). The primary end point was mean change in mean number of monthly migraine days during the 12-week period after the first dose. Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95% CI, -2.01 to -0.93 days; P < .001) and with single higher dosing vs placebo of -1.3 days (95% CI, -1.79 to -0.72 days; P < .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy. clinicaltrials.gov Identifier: NCT02629861.

Pseudomonas putida improved soil enzyme activity and growth of kasumbha under low input of mineral fertilizers

ABSTRACTEffective management of the nutrients and enzyme activity in the soil is necessary for maximum crop growth and productivity. However, the excessive use of chemical fertilizers (CFs) not only adversely affects the soil nutrient status and soil physicochemical properties but also aids pollution to the ecosystem. The objective of present study was to investigate the effect of single as well as combined applications of phosphate-solubilizing bacteria and agrochemicals on important soil enzyme activities and their impact on the growth of kasumbha (safflower). Pseudomonas putida (P. putida;106 cells/mL) was applied as seed inoculation prior to sowing, and CFs were applied as full, half, and quarter doses during sowing to modulate the growth of kasumbha host plants. P. putida in combination with half dose of CFs (PH) increased the soil urease and phosphatase activities, while P. putida combined with quarter dose of CFs (PQ) augmented the soil invertase activities. Moreover, the PQ treatment exhibited the maximum colony-forming units of P. putida. Leaf chlorophyll, carotenoids, protein contents, and root lengths were increased by PH treatment. Whereas, shoot length and leaf area were improved by PH and PQ treatments, respectively. Leaf protease activity was enhanced by P. putida in combination with full dose of CFs and PQ treatments, while leaf phosphate contents were significantly improved by PQ treatment. It can be concluded that P. putida in combination with half as well as quarter doses of CFs is a promising approach for the improvement of soil enzyme activities and growth of kasumbha and replacing 50% of the use of CFs.

Assessment of Heparin Anticoagulation Measured Using i-STAT and Hemochron Activated Clotting Time

Adequate anticoagulation, measured using activated clotting time (ACT), is important during vascular and cardiac surgeries. Unfractionated heparin is the most common anticoagulant used. The purpose of this analysis was to compare the i-STAT ACT (iACT) to the Hemochron ACT (hACT), both of which were then compared to anti-factor Xa (anti-Xa) assay, a representation of heparin level and activity. Prospective study. Tertiary care cardiovascular center. Eleven consecutive elective adult cardiac surgical patients. Prior to cardiopulmonary bypass, ACTs were measured using i-STAT and Hemochron technologies and compared to each other and to anti-Xa assay prior to and during a cumulative administration of heparin. Data were compared using bias analyses. Heparin (300 U/kg) was administered in quarterly doses. Coagulation labs were collected prior to and 3 minutes after each quarterly dose of heparin. The baseline ACTs for i-STAT and Hemochron were 147 and 142 seconds, respectively. A significant association was found between iACT and hACT (p = 0.002). The iACT measurements underestimated hACT at ACT levels >180 seconds or anti-Xa levels >0.75 U/mL. No significant difference was found between ACT data at anti-Xa levels <0.5 U/mL. There was a good association between the iACT and hACT; however, the 2 tests are not equivalent. Overall, the iACT underestimated the hACT. Agreement between the ACT technologies was good at lower ACTs and anti-Xa levels, but declined with an anti-Xa >0.75 U/mL.