Metabolic, hemodynamics and performance of traditional resistance training vs. Ponto zero method - Juniper Publishers

 Physical Fitness, Medicine & Treatment in Sports - Juniper Publishers

Abstract

The purpose of this study was to compare metabolic, hemodynamic and performance of traditional (TRA) resistance training vs. Ponto zero method. Sixteen recreationally trained men (26.6±5.1 years old; 83.4±13.9 kg; 176.7±7.1cm; 26.60±3.39BMI) participated in this study. Subjects visited the laboratory four times, in which the first visit, anthropometrics data was measured, and the second visit consisted of 10 repetition maximum (RM) test performed in the elbow flexion with straight bar. In the TRA protocol, subjects were oriented to flex their elbows in the concentric phase and fully extend, back to the starting position, during subjects the eccentric phase. In the Ponto zero, five-seconds of isometric action was used in the 120º elbow flexion in each repetition. In both protocols, subjects were instructed to perform three sets of 10 repetitions with 60% of 10 RM and two-min rest interval between sets. The volume load (total repetitions x load) was the same between conditions, however, Ponto zero showed significantly greater time under tension (TUT) and rating of perceived exertion (RPE) in all sets when compared to TRA (p <0.001). Blood lactate increased significantly only immediately after session in the TRA (p =0.015), and Ponto zero increased significantly immediately after, 30-min and 60-min time-points (p < 0.001). Similar reductions in diastolic blood pressure was observed in both sessions (p< 0.05). In conclusion, Ponto zero seems to be a good alternative of method to increase TUT, RPE and metabolic stress.

Keywords: Metabolic; Hemodynamic; Anthropometrics; Fernando Sardinia; Elbow flexion; EF exercise; Baseline

Abbreviations: RT: Resistance training, TUT: Time under tension; RPE: Rating of perceived exertion; ROM: Range of motion; EF: Elbow flexion; RM: Repetition maximum

Introduction

Resistance training (RT) methods has been widely investigated in literature as a possibility of manipulation of prescription [1-3]. Previous studies showed benefits of RT methods in development of muscle hypertrophy [4,5], strength [6,7], power [7] and muscular endurance [5]. In addition, studies showed that the greater acute stress of these methods with greater muscle swelling, lactate (La-) concentrations and rating of perceived exertion (RPE), which can contribute to adaptations related to RT [4,8]. In this sense, the Ponto zero is growing popularity and widely used by bodybuilders as a possibility to increase training intensity without increase the load. The method was created by a Brazilian competitor and coach Fernando Sardinia and consists in an isometric sustained contraction at the end of the movement in a total duration of five seconds in each repetition. This sustained contraction is at the point of greater moment arm, and the movement is not executed in a full range of motion (ROM). This partial ROM has been suggested that may not compromise muscle hypertrophy [9-11] but has an angle-specific adaptation for muscle strength [11]. Besides that, the addition of an isometric action in the point of greater moment arm can increase the time under tension in the point of greater force production, mainly in single-joint exercises, which the muscle of interest is the primary mover [10].

Time under tension (TUT) should consider the contraction velocities of different phases of movement (concentric and eccentric) and if there is an isometric contraction, as proposed by Ponto zero [10]. Previous studies suggested that greater TUT increase metabolic stress, which generally is measured by post exercise blood La- [4,8]. Recently, studies measured muscle thickness to indicate cellular swelling because of increased metabolic demand and related to chronic hypertrophy [8,12,13]. In addition, alterations of post exercise blood pressure (BP) and heart rate (HR) is observed as consequence of increased blood flow to the active muscle do deliver substrate and remove metabolites. Thus, RT methods that promote acute metabolic stress can be advantageous for chronic adaptations [8,12,13]. Based on it, the aim of the present study was to compare metabolic, hemodynamic and performance of traditional (TRA) vs. Ponto zero RT methods performed in a single-joint exercise. The initial hypothesis is that Ponto zero will promote greater metabolic and hemodynamics alterations due to higher TUT.

Methods

Subjects

Sixteen recreationally trained men (26.6±5.1 years old; 83.4±13.9kg; 176.7±7.1cm; 26.60±3.39BMI) participated in this study [Table 1]. To be included, subjects should be trained in RT at least six months, between 20 and 35 years old and familiarized with elbow flexion with straight bar (EF) exercise. Were excluded of the study those with recent historical of injuries in upper body and using ergogenic agents. All subjects answered the PAR-Q questionnaire and if had any affirmative answer, subject was excluded. During experimental procedures, subjects were oriented to avoid any king of supplements, especially thermogenic, antioxidants and vitamins. Subjects that are using any kind of anti-inflammatory medicines were excluded.

For ethical procedures, subjects were oriented about all experimental procedures that they were submitted in a consent term that should be answered if they are in accordance with all conditions. This study was conducted in accordance with the norms of the Brazilian National Health Council, under resolution no. 466/2012, referring to scientific research on human subjects and the Helsinki Declaration. This study was approved by University Ethic Committee under the number 28461920.1.0000.5257.

Experimental Approach to the Problem

This was a within-subjects repeated-measures study, in which all subjects visited the laboratory four times, separated by 48-72 hours. During the first visit, anthropometrics measures (height and weight) was measured and subjects were oriented about all experimental procedures. In addition, the first visit was used for familiarization session which participants performed the Ponto zero method in a total of three sets of 10 repetitions, with submaximal load, based on their training routine and 2-min rest interval between sets. In the second visit, 10 repetition maximum (RM) test was performed in the EF exercise. During sessions three and four, subjects underwent to two experimental protocols (TRA and Ponto zero) performed in a randomized crossover design.

Ten repetition maximum test

During the second session, subjects underwent 10RM to determine the load for the EF exercise [14,15]. The initial load was estimated based on the weight performed in the familiarization session. Before starting the test, one set was considered a warmup with 50% of the estimated load. Three to five attempts were used with three to five minutes of rest interval between trials. The higher load obtained was used in the experimental sessions. To reduce the margin of error during the test, the following strategies were adopted: 1) Standardized instructions were offered before the test so that the subject was aware of the whole routine that involves data collection; 2) The subject was instructed on the exercise execution technique; 3) The evaluator was aware of the position adopted by the participant at the time of the test, as small variations in the positioning of the joints involved in the movement could trigger other muscles, leading to erroneous interpretations of the scores obtained; verbal stimuli were performed to maintain a high level of motivation. The individuals were instructed not to ingest any stimulating substance (caffeine or alcohol) and not to perform physical activity on the day before or on the day of the tests [3,16]. The mean 10 RM load obtained was 37.5±6.8 kg.

Experimental protocols

In the EF exercise, subjects were oriented to position the arms extended along the body and the hands in a supinated position gripping a straight bar. In the TRA protocol, subjects were oriented to flex their elbows in the concentric phase and fully extend, back to the starting position, during subjects the eccentric phase. In the Ponto zero method, the ROM of the elbow flexion during the EF exercise was standardized prior session, with a goniometer, for each subject. A measure was taken in a lateral wall, in 120º of elbow flexion, for each subject to observe the moment arm that they should perform the isometric contraction (Figure 1). In both protocols, subjects were instructed to perform three sets of 10 repetitions with 60% of 10 RM and two-min rest interval between sets. In the Ponto zero, five-seconds of isometric action was used in the 120º elbow flexion in each repetition. If the subjects were not able to perform 10 repetitions with 60% of 10 RM in the Ponto zero, they were oriented to perform the following repetition without the isometric contraction. This strategy was adopted in order to promote a volume-equated condition between protocols (Figure 1).

Performance and Perceptual Response

For performance parameters, VL was measured using the following formula sets x repetition x load. The TUT was measured by visual analysis, which a 2d camera (PowerShot G7X Mark II; Canon®) captured each set duration and then it was analyzed in a software (Adobe Premiere PRO; Adobe Systems®). The TUT was considered the initial phase of the movement until the last repetition, returning the eccentric phase. Rating of perceived exertion was rated at the end of each set using OMNI-res scale, which 0 is considered an extremely easy set and rating 10 extremely hard set [17]. Metabolic Stress and Muscle Swelling. Blood Laconcentration was assessed via a lactate analyzer (Accutrend® Plus; Roche) at baseline, immediately after (approximately 30-seconds), 30-min and 60-min after exercise. First, the finger was sterilized with alcohol and cotton, then a puncture was made with a spring-loaded single use disposable lancet. The first drop of blood was discarded and the second was inserted in the analyzer. In addition to La- concentration, it was measured the relative difference between baseline and post exercise timepoints. Muscle swelling was measured with arm circumference in the right arm using a taper measure at baseline, immediately after (approximately 30-seconds), 30-min and 60-min after exercise. The arm circumference was measured at midpoint between acromion and olecranon and reported in millimeters.

Hemodynamics responses

Before each session, the baseline values of systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR were determined after a 10-minutes rest period, in a seated position. All measures were performed in an sociometric way (OMRON HEM-7113, São Paulo, Brazil), in the seated position and in the left arm. Post exercise measures were performed immediately, 15- min, 30-min, 45-min and 60-min after session.

Statistical Analysis

For statistical treatment, Sigma Plot 11.0 was used (Germany). The statistical analyses were initially performed using the Shapiro-Wilk normality test and homoscedasticity test (Barlett’s criterion). All variables showed normal distribution and homoscedasticity. A two-way repeated ANOVA with repeated measures was used to determine whether there were significant interactions between conditions at different time points for each protocol. For all measures, the Bonferroni post hoc was used to identify if there were significant differences and p≤0.05 was adopted for all inferential analysis. The Cohen’s d effect size was calculated and classified according to Rhea [18]. The formula consisted of the difference between the baseline values to postexercise values divided by the baseline standard deviation and classified as follows: <0.35 = trivial; 0.35-0.80 = small; 0.80-1.5 = moderate; >1.5 = large (Figure 2).

Results

Performance and Perceptual Response

Subjects were able to complete three sets of 10 repetitions with 60% of 10 RM in both conditions. Thus, the VL of 189.4±61.7 kg was the same between conditions. For the TUT, a main effect for set (F=7.742; p=0.002) and condition (F=3324.915; p<0.001) was observed, without significant interaction. Ponto zero showed significantly greater TUT in all sets when compared to TRA (p<0.001). For the RPE, a main effect for set (F = 49.821; p<0.001) and condition (F=120.273; p<0.001) was observed with significant interactions (F=3.987; p = 0.029). In the TRA, RPE was significantly greater in second (p<0.001) and third set (p< 0.001) when compared to the first set. In the Ponto zero, RPE was significantly greater in second (p<0.001) and third set (p<0.001) when compared to the first set. In addition, the third set was significantly greater than the second set (p = 0.002). In all sets, Ponto zero showed significantly greater RPE when compared to TRA (p<0.001 for all inferential analysis)

Metabolic Stress and Muscle Swelling

For the La-, a main effect for time was observed (F = 17.831; p < 0.001), without significant interactions. Blood La- increased significantly immediately after session in the TRA (p = 0.015). In the Ponto zero, La- increased significantly immediately after, 30- min and 60-min time-points (p < 0.001 for all inferential analysis). For the arm circumference, a main effect for condition was observed (F = 17.351; p < 0.001), without significant interactions. The arm circumference increased significantly immediately after session for both TRA (p = 0.001) and Ponto zero (p = 0.031) (Figure 3).

Hemodynamics responses

For SBP, a main effect for time was observed (F = 5.605; p<0.001), without significant interactions. Pairwise comparison did not reveal significant differences between baseline and post exercise time-points for both conditions. For DBP, a main effect for time was observed (F = 21.721; p <0.001). Significantly greater reductions in DBP immediately after (p < 0.001) and 15-min (p = 0.004) post exercise time-points when compared to baseline for TRA. In the Ponto zero, similar finding was observed with significant reduction of DBP immediately after (p < 0.001) and 15- min (p - 0.007) time-points when compared to baseline. For HR, a main time effect was observed (F = 3.088; p = 0.014), without significant interactions (Figure 4).

Discussion

The findings of this study revealed that although Ponto zero is a method without full ROM, the addition of an isometric contraction increased the TUT and interval load with greater increase in La- concentrations and RPE of the subjects. Alterations in muscle swelling, BP and HR were observed after session in both conditions, in a similar extent. In the present study, greater post exercise La- concentrations and RPE throughout sets in Ponto zero were attributed to greater TUT of this method when compared to TRA. Time under tension is generally manipulated with alterations in the cadence, slowing or accelerating the movement velocity of concentric-eccentric phases [19-22]. In a previous study, [23] compared a slow movement protocol (6- sec concentric and eccentric phases) with a traditional session with work matched (same number of repetitions). The results showed greater acute responses of myofibrillar, sarcoplasmic and mitochondrial protein synthesis rates when compared to traditional. Different from previous studies reported, Ponto zero increase the TUT in absence of full ROM and adding the isometric contraction in a point of great moment arm. This methodological approach contributes to explain the greater La- concentrations in this method. Although this suggests benefits considering muscle adaptations, specially hypertrophy, [24] reported no significant differences in the repetition duration for hypertrophy using 0.5-8 seconds, suggesting that although greater acute proteins synthesis, the chronic response is similar between slow movements and traditional.

Previous studies showed that in conditions of equalized TUT, protocols with greater VL and faster movements increases neuromuscular fatigue measured with electromyography and Laconcentrations. This is mainly attributed to the concentric phase performed in faster velocities recruit greater number of motor units than slower and this increase the metabolic demand. In another study [4] evaluated the metabolic stress in two protocols of sarcoplasm stimulating training (SST) method, which one consisted of greater TUT slowing concentric-eccentric phase and adding isometric contractions. No significant differences were observed for La- when compared to TRA. The main reason of this divergent finding is that in this study, the VL between conditions was equalized and in the study of Almeida et al. [4], greater VL was observed for TRA. It is important to highlight that Ponto zero was performed in conditions of submaximal load which suggests that the addition an isometric contraction in a point of great moment arm increase the internal load. In conditions of submaximal intensity, the increase in TUT seems to be beneficial to promote greater metabolic stress, increasing La-, and for muscle adaptations [20,21].

In the Ponto zero method, the partial ROM, with absence of the initial phase of the movement of EF, did not impaired the acute response of metabolic stress. Recent studies showed heterogeneous muscle adaptations when performing protocols with partial or full ROM. Alamitos et al. [11] compared partial and full ROM of knee extension in an isokinetic chair with equalized TUT. The results showed greater alterations in fascicle length and when performing full ROM, otherwise, partial revealed greater alterations in physiological cross-sectional area. In another study, Kubo et al. [9] compared hypertrophy and strength adaptations when performing partial and full depth in the squat exercise. When considering knee extensor muscle, both protocols elicited similar hypertrophy, however, full squat showed significant greater hypertrophy for gluteus maximus and adductor when compared to half squat. In addition, the study revealed an angle-dependent strength adaptation, which full squat improved 1 RM results in both full and partial ROM, while half squat improved only partial ROM. Recently, Schoenfeld and Gric [25] showed that the majority of evidences corroborate for full ROM for muscle hypertrophy when considering lower limb, and there is limited evidence when considering upper limb. 

In this study, the EF is a single-joint exercise, performed with free-weights, and all these variables should be considered. Significant hemodynamics alterations were observed in both conditions, especially considering DBP that reduced significantly immediately after session. This result suggests a vasodilatation after exercise with increase blood flow to the elbow flexors muscles [26,27]. Hemodynamics responses were modest specially by the low-volume session, which consisted of only one exercise, with three sets [28]. In addition, EF is an exercise that recruit small muscle groups, and multi-joint or lower limbs exercises shows greater hemodynamics alterations based on greater muscle involved [29,30] Probably a session with different exercises performed with Ponto zero or TRA should reveal different responses considering hemodynamics responses. A limitation of this study is the small sample size; however, subjects were selected according to their experience in RT and specifically in the exercise used in the protocols. In addition, only one exercise was used in this study, and future studies with Ponto zero should consider a session, with multiple sets and exercises. Future studies should consider evaluate the metabolic stress of different methods with additional biochemical measures [31].

Conclusion

Ponto zero RT method showed greater concentrations of La- attributed to longer TUT and greater RPE. Otherwise, both protocols showed increased metabolic stress markers after sessions, suggesting that both conditions should be used in a RT. The addition of Ponto zero must be considered in sessions that aim lower mechanical tension, in detrimental of the load, and greater metabolic stress.

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“Breaking Burnout: A Personal Reflection on Mindfulness Exercises for Physicians” - Juniper Publishers

Yoga and Physiotherapy - Juniper Publishers

Abstract

Burnout is frequently a problem for medical students, residents, and attending staff throughout all levels of training. Burnout reduction strategies are of particular focus given a severe shortage of physicians. This mini review article is a reflection of a previously skeptical resident who found that mindfulness activities were refreshingly effective in stress reduction and improving personal performance in patient care.

Keywords: Burnout; Mindfulness; Awareness; Yoga; Psychogenic; Stress; Anxiety; Dysthymia; Mood

Introduction

Physician burnout is an increasingly prevalent cause of clinical underperformance which inevitably negatively impacts patient care [1]. Interventions to alleviate physician burnout have included workshops for improving verbal communication, teamwork, and leadership skills [2-4]. Mindfulness activities such as reflection, sensory awareness activities, and Yoga for staff, residents, and medical students also reduce burnout at all levels of training [2-4]. The benefits of mindfulness and Yoga on stress management have also been demonstrated to extend broadly to nurses, teachers, police officers, and military personnel [5-10]. Unsurprisingly, mindfulness is an effective nonpharmacologic therapy for psychogenic disorders, dysthymia, and stress reduction in the general population [11-13]. This article is a reflection on the writer’s personal experience with mindfulness, sensory awareness activities, and Yoga as part of the standard curriculum for pediatrics graduate medical education at Indiana University. Reduction of internalized anxiety and negative talk in the workplace was found to concomitantly promote resilience and restoration of effective clinical performance.

Discussion

My first experience with participation in mindfulness activities at work was initially met with cynicism. “What would using the next 20-30 minutes for nothing achieve on my long check list?”, I remember internalizing. At least the afternoon consisted of mindfulness activities, so the check list was not multiplying by the second as it would on the inpatient service or in clinic.

Our first activity was to be mindful of our thoughts as we were guided by our mentor with eyes closed in a quiet place. We were instructed to recall a conflict, emotional case, or other tumultuous circumstance and to analyze our thoughts. We first reflected on our anger, frustration, or worries at the thought of revisiting such times, though we were given tools to address and release these negative thoughts. We were instructed to acknowledge the emotions, to be curious about them for a time, and to let them go when we understood them well. We again practiced this with other negative emotions and even happily restless situations. With each round of this simple 3 step exercise, I saw the power of mindfulness for reflection, even if it was only a personalized internal debrief. I would recall an emotionally charged situation, analyze the emotion in a nonjudgmental fashion by identifying its existence and questioning its origin, and dismiss it to a seemingly distant and unnamed place where it no longer held its pungence.

The second exercise was to be mindful of our senses. We were each given wrapped Lifesavers. As the wrappers were opened, we were instructed to listen closely to the sounds that were made by the wrapping as we held and exposed the Lifesaver. We were reminded to be aware and grateful for our sense of hearing. How rarely did I notice such a small stimulus as the noise made by wrapping paper in a positive way? How many times in a conference had I tried to suppress the sounds of my wrapped bag of chips or crackers as I opened my food? I found it comical to be enjoying the sounds of the wrapper on my hands as I opened the Lifesaver yet focusing my thoughts on this everyday task was refreshing. We then removed the Lifesaver and took a moment to appreciate the beauty of its features. The perfectly rounded edges, the crafted letters, and the vibrant color were all to be inspected. We were instructed to be grateful for our sense of sight and to witness detail where we previously would have been neglectful for lack of time or habit. Then we placed the Lifesaver in our mouths with noses pinched and were mindful of the taste and sensation of the candy against the tongue and palate. How many times had I eaten in such a hurry without noticing delicious textures of food or tastes that were pleasant? We were reminded to be grateful for the senses of touch and of taste prior to the final portion of this activity. We unpinched our noses and through glorious retronasal olfaction experienced the full flavor of the candy. Isolating our senses of taste and smell which synergistically interweave their afferent inputs into flavor gave the simple task of eating the possibility of more complete mindfulness.

An introduction to Yoga was the final mindfulness task. We started with sitting comfortably with deep breathing in through our noses followed by brief hold and then out through our mouths. The custom of being mindful of breath at rest was also observed. We then would assume a pose such as arms extended, and feet spread to a comfortable distance with the same deep breathing exercises. Laying down with deep breathing, tripod, and on all four extremities while focusing on breathing were all performed in sequence. This focus on each breath centered my thoughts and distracted me fully from the many additional responsibilities and deadlines which previously were at the forefront of my focus. While the simple act of breathing was often relinquished to chemoreceptors and acidity through circulating carbon dioxide, volitional breathing through supratentorial focus seemed to break the never-ending pursuit of the next goal. The many bullets on my long checklist seemed far away, and I felt relief that I could always return to them at the end of the mindfulness activities. It is important for trainees to realize that there is always time to plan ahead and achieve. Time to utilize mindfulness and relieve burnout from continuous breakneck pace is only possible through volitional choice.

Though I entered the mindfulness session desiring to use that half hour to send emails, write notes, and read articles, I left the activities with renewed vigor and was prepared to do my work with twice the efficiency and half the stress.

Conclusion

Despite numerous responsibilities, tremendous pressure, and prolonged training, medical students, residents, and staff would find benefits from brief mindfulness techniques that are practiced periodically. Though it is initially hard to partition the time required for such activities, the efficiency boost from breaking burnout more than accounts for the time utilized for these activities for the writer. Spending 20-30 minutes initially can soon be pruned down to 3-5 minute sessions more frequently throughout the day with ease and without sacrificing efficacy. I am hopeful that this reflection resonates with others who feel the effects of burnout and helps them to experiment with mindfulness, awareness, or Yoga with deep breathing.

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The Influence of Computer Screens on the Blinking Rate A Comparison with and without a Screen - Juniper Publishers

 JOJ Ophthalmology - Juniper Publishers

Abstract

Purpose: Ocular and visual symptoms are felt by many subjects during computer use. Previous studies have reported a reduced blink rate during computer operation and suggested that this may account for some of the symptoms, particularly dry eye. However, these earlier investigations did not include a control condition. To determine whether it is computer screen viewing that produces the change in blink rate, the present study compared blink patterns when reading from either a desktop computer monitor or a hard copy printed text under equivalent viewing conditions.

Methods: Subjects (N=118) were asked to undergo a continuous 20-minute reading task from either a desktop computer screen or a printed page at the same viewing distance. Identical text was used in the two sessions, with similar size and contrast. Target viewing angle and luminance were similar for the two conditions. Subjects were videotaped during the task to determine their blink rate. Immediately after the task, subjects completed a questionnaire regarding ocular symptoms experienced during the trial.

Results: Mean blink rates for the computer and hard copy conditions were 14.64 & 13.12 blinks per minute, respectively (p < 0.001). A significantly higher score of ocular symptoms was observed for the computer condition (p < 0.001).

Discussion: Blink rates were not reduced during computer operation when compared with an equivalent hard copy control condition. Suggestions state that the previously observed differences in blink rate are more likely to be produced by changes in cognitive demand rather than the method of presentation. However, during the use of computers, a higher score of ocular symptoms was noted which may have been associated with visual tiredness.

Conclusion: The study aims to compare the rate of blinking with and without a screen, to know if screens cause an influence on the blinking rate. Results show the increase in the blinking rate is more remarkable with screen than without screen. Future studies must focus on increasing the blink amplitude to determine whether this provides a viable method of reducing symptoms during computer use.

Keywords: Ocular; Visual symptoms; Blink rates; Computer vision; Diopter; Autorefractometer; Electronic screen; Phoropter, Schirmer’s test strips, Fluorescein strips; Optotypes; Slit lamp; orthoptic problem

Keywords:

Introduction

Our excessive and increasing use of computers has led to the development of a number of health problems. In contrast, our need for paper has decreased. Eye discomfort, fatigue, and stress are some of many work-related complaints and symptoms reported by many people who work on a computer. As computer use increases, so does the level of discomfort. The visual discomfort and related symptoms that occur in computer users should be treated as a growing health issue. Thus, arises the “Computer Vision Syndrome” which is the complex of eye and vision problems associated with experienced work while using the computer. A blink poses an interesting phenomenon that should be monitored and studied. In addition to being an important tool for scientific research, blinking is a necessity for our well-being, because of its role as a protective barrier for the eye and as a distributor of the tear film on the ocular surface. The blink rate can be defined as the frequency during which spontaneous blinks occur and can be even used as a measure of visual fatigue. Several studies have shown that computer screens directly influence the blinking rate.

Between 64 & 90% of computer users experience visual symptoms, which may include eyestrain, headaches, ocular discomfort, dry eye, diplopic, and blurred vision either at near or when looking into the distance after prolonged computer use according to Thomson [1]. A recent investigation of computer users in New York City noted that 40% of subjects reported tired eyes “at least half the time”, whereas 32 & 31% reported dry eye and eye discomfort, respectively, with this same frequency [2]. Other studies have also found a strong association between dry eye and computer-related symptoms, with longer periods of computer work being associated with a higher prevalence of dry eye [3]. Investigations state that computer tasks reduce the blink rate [4-6]. Tsubota and Nakamori [4] compared the rate of blinking in 104 office workers when they were relaxed, reading a book, or viewing text on an electronic screen. Mean blink rates were 22 per minute while relaxed but only 10 per minute and 7 per minute when viewing the book or screen. These three testing conditions varied in the method of presentation and in task demand. It has been noted that as font size and contrast are reduced, blink rates are reduced as well [7] or the cognitive demand of the task increases [8,9]. Therefore, the differences observed by Tsubota and Nakamori [4] may be related to changes in task difficulty and are not the consequence of changing from printed material to electronic ones.

An important question arises: “Is the change in blink patterns during computer use related specifically to viewing the electronic screen or is it simply the result of performing a demanding nearvision task?”

Indeed, [10] states that both the visual nature of the task and the psychological status of the user should be considered in studies examining eye blink activity during computer use. Previous studies observing a reduced blink rate during computer use have not included an equivalent hard copy control trial, under the same viewing conditions. It has been suggested that the poorer image quality of the electronic screen may be responsible for the fluctuation in blink rate, when compared with printed materials. However, [7] observed that degrading the image quality by either inducing 1.00 diopter (D) of uncorrected astigmatism or presenting a target at only 7% contrast did not produce a significant change in blink rate for a given level of cognitive demand. Furthermore, [7] reported an increased blink rate when induced refractive error, glare, reduced contrast, and accommodative stress (varying the accommodative stimulus by ±1.50 D during the course of the task). In addition, [11] found that a significant reduction in blink rate is observed during the introduction of an antireflection film over a computer monitor to reduce glare produced. Since evidence lacks regarding the role of the electronic screen in the change in blinking rates, the aim of the present study was to determine if a difference in blink patterns exists when subjects perform similar reading tasks from either a computer monitor or printed materials.

Methods & Materials

The study involved 118 patients aged between 18 & 35 years. They were examined in an optometry clinic. Subjects included were those having a monocular visual acuity at least 10/10 for far and near, with or without optical correction. Subjects excluded were those having an uncorrected ametropia, having a squint or an orthoptic problem, having an eye pathology or dry eye, having undergone a previous eye surgery, patients suffering from a general pathology influencing the visual system such as diabetes, high blood pressure, etc.

The examination room was equipped with a slit lamp, an autorefractometer, a digital phoropter, Schirmer’s test strips, fluorescein strips, a projector of optotypes, a laptop, printed papers and a video camera. The recruited patient was received in a quiet room, with moderate lighting, of moderate temperature, without ventilation or any other factor that could hinder the examination of tear secretion and refraction. The contrast on the computer screen and the printed paper was the same. Figure 1 the text read had the following characteristics identical on both computer and paper: Size 14, Font Times New Roman, Black color, a single space between words. Subjects wearing contact lenses got rid of their lenses before 48 hours of our experience. Subjects were not informed that their blinks were being monitored or recorded as this could cause voluntary blinks. All of the subjects were interviewed to fill out their examination sheets to ensure first of all their age and the absence of any ophthalmological and general history.

We started with the study of lacrimal secretion with the Schirmer test (normal if more than 15mm per 5 minutes) and the B.U.T. (normal if break after 10 seconds). Then, we performed orthoptic tests including the motility test, PPC (Punctum Proximum Convergence), cover/uncover test. These tests must be within the normal limits. Visual acuity from far and near, raw and with correction, was measured monocularly and binocularly. It must be at least 10/10. To ensure that the patient is emmetropic or perfectly corrected, we performed refraction. It was preceded by a measurement on the autorefractometer. After completing the information and carrying out the tests mentioned above, we made the experience concrete, divided into two phases of 20 minutes each, and separated by an interval of at least 24 hours.

The patient read identical text on a laptop screen during the first phase and on printed paper during the second phase. During these two phases, the subjects’ eyes were filmed using a video camera from a cell phone (smartphone), held by a support. Sufficient material was provided for 20 minutes of reading without repetition. The recorded videos allowed us to count the number of blinks during each phase. The results of the number of blinks enabled us to determine the blink rate per minute. Immediately after completion of each reading task, subjects completed a written questionnaire asking about their level of ocular symptoms observed during the two sessions. The results were recorded on a scale ranging from 0-10 (0: zero, 10: severe).

Statistical test:

The statistical test adapted in the study is the “analysis of variance” as known as ANOVA. It is a test that is applied when one or more discrete explanatory variables (the factors) that influence the distribution of a variable continue to be explained. We can compare Sig (The degree of significance) with α = 5% (The risk of error). If Sig < α The qualitative variable has an effect on the quantitative variable.

Result

Population Study

This part includes a descriptive presentation of the variables studied throughout this study.

We considered 118 patients of an age group [18-35], taking into account the theoretical increase in dry eyes, the decrease in the blinking rate and the appearance of presbyopia with age. The average age is 26.72 years with a standard deviation of 4.563. The distribution of the population by gender was 56.78% male and 43.22% female. 66.90% were emmetropes and 33.10% were corrected ametropes [Tables 1-8]

The full population study can be found in Appendix A.

Results

Without screen:

Males and females are almost equal.

P-value = 0.563 > 0.05

The variations are slight between all professions.

P-value = 0.534 > 0.05

The 2 refractive state groups are almost equal.

P-value = 0.943 > 0.05

With screen:

The majority of the subjects are males.

P-value = 0.07 > 0.05

The majority are indoor workers.

P-value = 0.135 > 0.05

The majority are perfectly corrected ametropics.

P-value = 0.104 > 0.0

Symptoms

The ANOVA test carried out between the symptoms and the experience “without screen” or “with screen” shows us that there is a relationship between these two variables P-value ≤0.05. The majority of subjects without a screen have a rate of 13.20 and subjects with a screen have a rate of 15.30 (see Appendix D). The average blink rate without and with screen are respectively 13.1161 and 14.6381. This means, as shown in the diagram, that the average blinking rate with screen is slightly higher than that without screen. The ANOVA test shows us a significant variation P-value 0.00 < 0.05.

Results Analysis

The aim of this research was to study the influence of computer screens on the rate of blinking and the symptoms observed. This was based on a comparison of the results obtained by reading an identical text on a screen and on a printed paper, since the influence of the screens causes a variation in the rate of blinking and the appearance of symptoms. This work was carried out on 118 subjects aged between 18 & 35, average is 26.72. 66.90% were emmetropes against 33.10% ametropes perfectly corrected? Thus, this margin of difference allowed us to establish a comparative study between the emmetropes and the ametropes perfectly corrected. All patients underwent the test with and without a screen. The average blink rate among emmetropics was 13.12 without screen versus 14.50 with screen. Whereas in perfectly corrected ametropics, the average was 13.10 without screen against 14.91 with screen. Fifty-six-point seventyeight percent of the subjects were males and 43.22% were females. Thus, this margin of difference allowed us to establish a comparative study between males and females. All patients underwent the test with and without a screen.

The average blink rate for males was 13.17 without screen versus 14.82 with screen. Whereas in females, the average was 13.04 without screen against 14.39 with screen. By studying the significance (p-value) without screen according to sex (p-value = 0.563 > 0.05), the refractive state (p-value = 0.943 > 0.05) and the profession (p-value = 0.534 > 0.05), we conclude that the variations are not significant. On the other hand, by studying the significance (p-value) with screen according to sex (p-value = 0.07> 0.05), the refractive state (p-value = 0.104 > 0.05) and the profession (p-value = 0.135 > 0.05), we deduce that the variations are also non-significant.

Compared to the symptoms found without a screen, we note blurred vision scores while looking at text 0.41, blurred vision looking from afar at the end of the task up close 0.36, difficulty / slowness in refocusing eyes from one distance to another 0.35, irritated or burning eyes 0.75, dry eyes 1.00, eye fatigue 1.03, eye discomfort 1.04, photophobia 0.22 and headache 0.40. On the other hand, we find with screen an increase in the scores of all the symptoms (Figure 2): blurred vision while looking at text 1.21, blurred vision by looking from afar at the end of the task near 0.78, difficulty / slowness in refocusing eyes from one distance to another 0.73, irritated or burning eyes 1.95, dry eyes 2.98, tired eyes 3.29, eye discomfort 3.18, photophobia 0.77 and headache 0.85. The ANOVA statistical test shows a significant variation (p-value < 0.05) for the 9 symptoms. The variation of the average blink rate with screen is 14.63, greater than that without the value 13.11 screen. There is a significant variation according to ANOVA, p-value = 0.00 < 0.05.

Discussion

The total symptom score was higher regarding the computer condition. However, between the 2 presentation methods, the overall blink rate was not notably different. The absence of a reduction in blink rate with computer use is contrary to previous reports [4-6]. As noted earlier, these previous investigations did not include an equivalent hard copy control trial. In the present study, the hard copy condition was performed at the same viewing distance and gaze angle and comprised the same reading material while both target contrast and letter size were matched as closely as possible. Since no difference was noted between the two conditions, this would imply that the differences reported previously were caused by variations in task demand rather than being produced directly by the computer monitor. For example, [4] found a significantly lower rate of blinking in office workers viewing text on an electronic screen compared with when they were relaxed. [13]. observed a reduced blink rate when the subjects were performing a computer task compared with “general conversation”. In all cases, the increased cognitive demand of the computer task could account for the change in blink rate reported previously. Accordingly, evidence lacks to support the proposal that performing a task using an electronic monitor will produce a change in blink rate compared to carrying out the same task using printed material.

A review by Doughty [2] noted environmental conditions affect the blink rate (e.g., ambient temperature and humidity), gaze angle, and verbalization. Although the environmental conditions were not strictly under control, all of the experimental sessions were conducted in the same clinic, with variations in temperature or humidity levels. Both gaze angle and verbalization (i.e., the requirement to read the text aloud) were the same for both conditions. Doughty [2] suggested that reading aloud (as opposed to sitting in silence) might represent a “subtle stimulus” to blinks, so one might conclude that slightly different results could be reached if the subject read silently which is the popular case in work environments. Although verbalization has been shown to increase the blink rate, [12,13], moving the jaw on its own does not significantly affect the blink rate [14]. Accordingly, task difficulty may form some sort of relationship between blink rate and speech [14-18]. It seems reasonable to assume that, no significant difference in blink rates between the computer and hard copy conditions would have been noted even if the subjects had read silently rather than aloud.

Conclusion

The aim of this study is to compare the rate of blinking with and without a screen, in order to know if screens cause an influence on the blinking rate and on the symptoms related. According to the results, the increase in the blinking rate is more remarkable with screen than without screen. By focusing on the symptoms observed, we notice an increase of the scores with the computer screen. The difference observed can be attributed to the demand for the reading task, which is more complex on the computer screen than on paper. This allows us to conclude that the symptoms present a more severe score on the computer screen, as well as a slight increase in the rate of blinking.

It shows that under tested conditions, no significant change in blink rate is observed when using computers exclusively. The level of cognitive demand is likely responsible for blink rate decline. As mentioned before, increased symptoms during computer operation were associated with a higher percentage of incomplete blinks, future studies must focus on increasing the blink amplitude to determine whether this provides a viable method of reducing symptoms during computer use.

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A Novel and an Alternative in vitro Release Test for Hydrophobic Diflorasone Diacetate Ointment with Dialysis Method by using Reciprocating Cylinder, USP Apparatus 3 - Juniper Publishers

 Pharmacy & Pharmaceutical Sciences - Juniper Publishers

Abstract

A novel and reproducible in vitro release test method was developed for the performance assessment of an ointment formulation containing an anti-inflammatory drug substance called as Diflorasone Diacetate which is insoluble in water and its performance comparison with a reference drug product. in vitro release test was performed by using Reciprocating Cylinder known as USP Apparatus 3, alternatively to Franz Diffusion Cell and Flow Through Cell. Experiments were designed to evaluate the effect of the composition of receptor media containing phosphate buffer pH 5.8: Ethanol under the conditions at 32ºC±0.5, 20dpm for 24 h. A dialysis membrane was evaluated: 12-14 KD MWCO, which is inert and practical. Experimental results indicated that the release amount of drug substance increased when ethanol ratio was higher. The requirement for the similarity between the generic dermatological preparation, which is corticosteroid in potent group Ⅲ with ATC code D07AC10 (AI Drug)* and Dulozafone Diacetate Ointment 0.05 % (RLD)** based on USP <1724> monograph for in vitro release performance has been provided.

Keywords: in vitro; Release; Performance tests; Semisolid; USP apparatus 3; Ointment release; Diflorasone diacetate; Franz diffusion cell; Flow through cell dialysis

Introduction

A dosage form according to the USP pharmacopoeia is a pharmaceutical preparation consisting of drug substance (s) and / or excipient (s) to facilitate the dosage, administration and administration of drug product or placebo ingredient to the patient. [1]. Topically applied drug products are examined in two general categories. The first of these categories are those applied to provide local effect and the other is applied to achieve systemic effects after being absorbed into the bloodstream through the skin [2]. One of the advantages of administering drugs to the patient through the skin is that it can provide controlled and continuous application of the drug. In addition, drugs with short biological half-lives are ensured in continuous application. [3].

The most important similarity parameter for any drug product is its efficacy, as demonstrated in controlled clinical studies. When such trials are evaluated considering time and costs, they cannot be used as a routine quality control method and performance measurement. For this reason, in vitro testing is often used to ensure that product quality and performance is maintained over time and whenever there is a change. Various physical and chemical tests performed for semi-solid products and their components provide reasonable evidence of consistent performance in the past [4].

For pharmaceutical products, semisolid dosage form quality control tests include identification, assay, impurities, viscosity, particle size, and testing. An in vitro release test is used to monitor the release and diffusion of drug products from semisolid dosage form [5]. An in vitro release rate reflects the combined effect of several physical and chemical parameters, including the solubility of the active ingredient, particle size, and rheological properties of the dosage form. The in vitro release rate is a useful test to evaluate product identity between products before and after exchange [4]. in vitro methods allow the use of synthetic membranes and animal or human skin (biological membrane), and contribute toward the reduction, refinement, and replacement of in vivo testing.

in vitro release comparisons are based on recommendation texts described in the United States Food and Drug Administration (FDA) Draft Guidelines for acyclovir ointment [6] and the SUPACSS Guidelines for non-sterile semi-solid dosage forms [4]. Plots of release rates (slopes) of cumulative amounts of acyclovir released versus square root of time for various generic formulations compared to the reference product in the Draft Guide for acyclovir ointment were found to range from 75.00% to 133.33% with a 90% confidence interval. These experiments show that generic acyclovir cream formulations exhibit release rates comparable to the innovative product and can be considered pharmaceutically equivalent [5].

Vertical Diffusion Cell Apparatus and USP Apparatus 4 (Flow Through Cell) are recommended in USP <1724> monograph for in vitro release test for semisolid drug products to carry out the performance tests. Also for semi-solid dosage forms in same monograph, it is stated that they are acceptable as extended release preparations [7]. Therefore, USP Apparatus 3 (Reciprocating Cylinder) device recommended for in vitro performance tests of extended release drugs can be used by placing the sample in a dialysis bag membrane.

A thick layer of semi-solid product is placed in contact with a medium in a reservoir. Diffusion takes place across an inert, highly permeable support membrane. The membrane needs to keep the product and the receptor environment separate and different. Membranes should offer the least possible diffusion resistance. In addition, the membranes should not be speed controllers [7]. Diflorasone Diacetate is a topically applied drug in the ointment dosage form on the market. It is used in the treatment of psoriasis and eczema as an indication. Diflorasone Diacetate is in a class of drugs called corticosteroids. It works by activating ingredients in the skin to reduce swelling, redness, and itching [8].

Diflorasone Diacetate can be absorbed through the skin and entered the systemic circulation. After absorption through the skin, topical corticosteroids are used in pharmacokinetic routes like systemically administered corticosteroids. Corticosteroids bind to different degrees of plasma proteins. They are primarily metabolized in the liver and then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted in bile [9]. In this study, performance similarity of AI Drug and RLD was evaluated by using Franz Diffusion Cell and Flow Though Cell (USP Apparatus 4) recommended in USP <1724> monograph; alternatively, by using Recipricating Cylinder Apparatus (USP Apparatus 3).

Materials and Methods

Materials

a. Diflorasone Diacetate RS, 99.5% purity was purchased from USP (Maryland, USA)

b. Acetonitrile (JTB, USA; Catalog Number:104873)

c. Ethanol ( Fisher, Hampton, USA; Catalog Number: E/0600DF/F21)

d. Sodium Hydroxide ( Sigma, Missouri, USA; Catalog Number:06203)

e. Potassium dihydrogen phosphate (Merck, Darmstadt, Germany; Catalog Number:104873)

f. Dialysis membrane 12-14 KD MWCO was purchased

g. Glass Microfiber Filters Diameter 25 mm, GF/D (Whatman)

h. Cellulose Acetate Membranes, 0.45 μm (Whatman)

Equipment’s

a. Franz Diffusion Cell Apparatus (Hanson)

b. Flow Through Cell Apparatus, USP Apparatus 4 (Sotax)

c. Reciprocating Cylinder Dissolution Apparatus, USP Apparatus 3

d. Waters High Performance Liquid Chromatography equipped with an ultroviolet/visible dedector Waters 2489;

a reversed phase column: Waters Symmetry C18 150 mm x 4.6 mm x 3.5 μm; a data recorder and processor system: Empower Software.

Composition of the formulations

AI Drug was developed by Abdi İbrahim R&D Center, Turkey. RLD was used as reference product was obtained from Taro Pharmaceuticals Inc, Canada. The composition of the formulation contain; Diflorasone Diacetate (Drug Substance), Propylene Glycol (softener), Glycerol (emulsifier), Vaseline (ointment base).

Methods

Preparation of samples

Dialysis membranes in appropriate length were cutter and saturated with receptor media. One side of the membrane was clamped with a dialysis clamp and filled with the ointment sample. Then, the other side of the membrane was clamped with a dialysis clamp, depicted in Figure 1. Each dialysis sample was prepared by carrying out this procedure and placed into the each vessel.

Release determination

The release profiles of AI Drug and RLD were measured at 32ºC ± 0.5 °C with using different ratio of receptor media containing phosphate buffer pH 5.8 and ethanol for 24 h, 20dpm (sampling time: 1h, 3h, 6h, 9h, 12h, 18h ve 24h) by Reciprocating Cylinder Dissolution Apparatus (USP Apparatus 3). Volume of receptor media 250 ml per each vessel. The receptor compartment was not renewed with the solution; therefore, cumulative calculation was used for the determination of the results obtained from HPLC method.

HPLC method

The mobile phase was a mixture of acetonitrile and water (50:50, v:v). Mixed well and degassed before application. Experimental conditions were as follows: Injection volume 50μl; the mobile phase performed isocritically pumped at a flow rate 1.0 ml/min; column temperature 25°C; sample temperature 5°C; the detection wavelength 254nm. Method validation has been successfully completed by applying specificity, linearity and range, precision, accuracy and recovery, robustness parameters to in vitro Release Test method in Diflorasone Diacetate 0.05% Ointment.

According to validation studies results: in vitro Release Test method is specific for Diflorasone Diacetate and robust in view of changes to flow rate, wavelength, column temperature. The linearity, accuracy and recovery of the method in the range of 0.0004mg/ml – 0.0060mg/ml has been proved.

Method Development Receptor Media Selection

It is necessary that drug substance have a sufficient solubility in the media throughout the study without an effect on sink conditions while choosing a compatible receptor media for in vitro release test. Especially for the drug substances which has lower solubility characteristics in water, the aqueous buffer solutions or hydro-alcoholic medias can be used as a receptor solvent with an appropriate justification [10]. Any receptor media for release performance of the ointments containing Diflorasone Diacetate has not indicated by FDA or any pharmaceutical guideline. Therefore, the points below were considered to choose of the receptor media:

A. Determination of Diflorasone Diacetate solubility in the solutions

B. Determination of the hydrophobic / hydrophilic characteristics of the excipients

C. Determination of appropriate pH value, considering the indications of the drug and its target area

While selecting of the receptor media it was considered that oil of skin, sweat glands and fatty acid breakdowns by Staphylococcus brings about a slightly acidic pH value for human skin. Therefore, phosphate buffer pH 5.8 was chosen as a main component of the receptor media [11]. Diflorasone Diacetate is a white to pale yellow crystalline powder which is soluble in methanol and in acetone, sparingly soluble in ethyl acetate, slightly soluble in toluene, very slightly soluble in ether and insoluble in water [12]. Besides, the excipients in the formulation were evaluated. Propylene Glycol is miscible with water and with ethanol (96%) [13]. Glycerol is miscible with water and with ethanol (96%), slightly soluble in acetone practically insoluble in fatty oils and in essential oils [14]. Vaseline is insoluble in water, soluble in dichloromethane, chloroform, benzene, diethyl ether, carbon disulfide and turpentine [15]. In result, addition of an alcoholic structure to the receptor media was decided. Ethanol was selected because of high amount solubility of Diflorasone Diacetate in alcoholic structures, high amount vaseline in the ointment formulation which has an insoluble characteristic in water and the other excipients which are miscible with ethanol.

Receptor Media and Apparatus Selection

Vertical Diffusion Cell Apparatus and USP Apparatus 4 (Flow Through Cell) are recommended in USP <1724> monograph for in vitro release test for semisolid drug products to carry out the performance tests. Therefore, both were used to evaluate the release of the formulations in this study. In addition to that, USP Apparatus 3 (Reciprocating Cylinder) was alternatively used to determine the release performance.

Phosphate buffer pH 5.8

Diflorasone Diacetate raw material and reference standard were insoluble in phosphate buffer pH 5.8 based on its insolubility in water. In result, phosphate buffer pH 5.8 100 % was not selected as a receptor media.

Phosphate buffer pH 5.8: ethanol (80:20, v/v) and phosphate buffer pH 5.8: ethanol (50:50, v/v)

Firstly, both Franz Diffusion Cell and Flow Through Apparatus were used to perform in vitro release test for AI Drug and RLD with phosphate buffer pH 5.8: Ethanol (80:20, v/v) and phosphate buffer pH 5.8: Ethanol (50:50, v/v) as receptor medias. The studies were carried out by 0.45 μm cellulose acetate synthetic membranes and 25 mm microfiber filters for Franz Diffusion Cell and Flow Through Apparatus, respectively. There was no significant data for each study because of inability of release from the membrane surface, given in Table 1.

Alternatively, in vitro release studies were performed by using Reciprocating Cylinder, USP Apparatus 3, on AI Drug and RLD with phosphate buffer pH 5.8: Ethanol (80:20, v/v) as a receptor media under the conditions at 32ºC±0.5, 20dpm for 24 h. The release was achieved with dialysis membrane 12-14 KD MWCO. Main calculated cumulative release of Diflorasone Diacetate (%) reached 11.2 % and 11.8 % at 24 hours respectively. When the dissolved amounts are considered for each period, both ointment formulation showed similar relationship between calculated cumulative release versus time. Results of phosphate buffer pH 5.8: ethanol (80:20, v/v) study were given in table 2 & figure 2.

Furthermore, in vitro release studies were performed by using Reciprocating Cylinder, USP Apparatus 3, on AI Drug and RLD with phosphate buffer pH 5.8: Ethanol (50:50, v/v) as a receptor media under the conditions at 32ºC±0.5, 20dpm for 24 h. The release was achived with dialysis membrane 12-14 KD MWCO. The results of phosphate buffer pH 5.8: ethanol (50:50, v/v) study was given in table 3, Table 4 & Figure 3. The results proved that main cumulative release of Diflorasone Diacetate (%) was higher when the receptor media phosphate buffer pH 5.8: ethanol (50:50, v/v) was selected. Due to increase in ethanol ratio of the receptor media, Diflorasone Diacetate cumulative release (%) reached 23.6 % and 24.4 % at 24 hours for AI Drug and RLD, respectively. Hence, phosphate buffer pH 5.8: ethanol (50:50, v/v) was finalized as receptor media for in vitro release test study

Experimental results showed that USP Apparatus 3 can be used to evaluate the performance of the drug products as an alternative method of Franz Diffusion Cell and flow Through Cell. Besides, the release amount of drug substance increased when ethanol ratio was higher. Therefore, Reciprocating Cylinder USP Apparatus 3 was selected and phosphate buffer pH 5.8: Ethanol (50:50) was chosen as receptor media for in vitro release test.

Results and Discussion

These studies were carried out based on USP <1724> monograph to monitor in vitro release performance of different ointment formulations, which were AI Drug (Batch Number: 6261806P1 & 6261806P2, manufactured by Abdi İbrahim İlaç San. Ve Tic.A.Ş) and RLD (Batch Number: J768529434, manufactured by Taro Pharmaceuticals Inc.) and prove the similarity in the release rate of the drug substance for phosphate buffer pH 5.8: Ethanol (50:50, v/v) receptor media under the conditions at 32ºC±0.5, 20dpm for 24h. Each ointment formulation was tested for the release of the drug through a dialysis tubing membrane and showed an ability to release Diflorasone Diacetate active substance from the membrane surface. Tables 5 & 6 show the results of the cumulative release amount for the different formulations as a function of time. Table 7 show mean cumulative release amount by time for three ointment formulations. Cumulative release amount vs square root of time graph for each formulation is depicted in figure 4. As a result, it can be stated that each formulation gives almost parallel released amount after 6h period by reaching 13.7 %, 13.9 % and 12.9 % respectively.

To acquire a quantitative approach on the performance of the generic drug products, the amount of drug released (%) at each sampling time (t1, t2, etc.) is determined for each vessel and the cumulative amount released plotted versus square root of time. The momentary rate of the release for the drug substance, which is dm/dt, becomes proportional to 1/√t, which mirrors the slowing of drug release in the course of time. The slope of the cumulative release versus square root of time graph gives the rate of drug release [7]. The average value of 6 slopes from the graphs for each formulation is a measurement of the drug release rate from the test products and reference product.

The Mann-Whitney U test is used to determine the 90% confidence interval for the ratio of the slopes between the test and the reference products. The T/R slope ratios are calculated for each test-to-reference slope, which test batch is T and reference batch is R. The calculations are given with a table where the values for the slopes for test product and reference product are listed down the left side and across the top of the table, respectively. Then, The T/R slope ratios are calculated by multiplying 100. After the T/R ratios have been determined, the results are ordered from the lowest one to the highest one. The 8th and 29th T/R ratios must be within the range of 75.0 %–133.33% [7].

Cumulative release (%) versus square root of time graphs (√t) plotted and their slopes for each vessel are given in figures 5-7. The ratio of the slopes between test batch and reference batch is listed in tables 7 & 8 and the summary is shown in Table 9. As a result, the performance test for AI Drug (batch numbers: 6261806P1 & 6261806P2) over RLD (batch number: J768529434) was accomplished. The slopes obtaining from the graphs for each vessel was calculated for each formulation. The T/R ratios was then determined. The 8th and 29th T/R ratios are identified. The ratios were between the range of 75.0 %–133.33% for both comparative studies.

Conclusion

A novel and alternative in vitro release test method was developed for the ointment formulations, which have a hydrophobic characteristic impacting ability of release for drug substance from the product in a negative way, included Diflorasone Diacetate drug substance which is insoluble in water. The performance of the generic formulati

ons against the reference drug was evaluated and similarity between the formulations based on USP <1724> was provided.

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Reading Comprehension in Students with Autism Spectrum Disorder: The Role of Metacognitive Skills, Motivation, and Use of Strategies - Juniper Publishers

 Intellectual & Developmental Disabilities - Juniper Publishers

Abstract

The purpose of the present exploratory study is to relate reading comprehension, metacomprehension skills, motivation for reading, and use of strategies among a group of students with autism spectrum disorder and their typically developing peers. More specifically, the aim was to determine which aspects can best explain performance in reading comprehension. Eighty-two students who were in the eighth grade to the fourth year of high school participated. They completed a standardized reading comprehension test, answered metacognitive measurement instruments, metacognitive monitoring, a questionnaire on motivation for reading, and a protocol for thinking aloud. According to the results, we conclude that metacognitive skills, motivation and use of strategies significantly predicted performance in reading comprehension in students with ASD, and that there were some interesting differences between this group of students and their typical peers.

Keywords: Autism spectrum disorder; Reading comprehension; Metacomprehension skills; Motivation for reading; Comprehension strategies

Introduction

Autism Spectrum Disorder (ASD) is conceptualized as a disorder that is characterized by difficulties in social interaction, communication, and repetitive and restricted behaviors and interests [1]. Based on these characteristics, the literature in recent years has described that this population presents limitations in reading comprehension, which cannot be explained as difficulties in the basic processes of access to the written code or cognitive development [2].

Reading comprehension is one of the most important skills to develop during the learning process. It supports the basis for the acquisition of future learning, thereby influencing personal development. However, controlling understanding and learning is challenging. Research suggests that some people’s ability to control or monitor their understanding is relatively poor [3,4].

Therefore, for individuals with ASD, in addition to making descriptions that account for their reading comprehension skills, it is essential to inquire about how they face their limitations and what challenges discourse processing imposes on them. According to research in neurotypical populations, the findings are conclusive in terms of the weight of metacomprehension, holding that it affects reading performance [5-8].

The present study aims to determine what aspects of metacomprehension skills, reading motivation, and metacomprehension strategies can better explain the performance in reading comprehension in students with ASD who are enrolled between eighth grade and the fourth year of high school. It accomplishes this via a quantitative and exploratory approach.

Materials and Methods

Eighty-two Chilean youths participated, 41 of whom were diagnosed with ASD and 41 from the TIP group, who were typically developing peers. This comparison between the participants with ASD and their neurotypical peers will serve to define whether the metacomprehension difficulties observed in the population with ASD are unique or, on the contrary, turn out to be like those of their typically developing peers.

Reading comprehension was measured with Lectum, a standardized measure developed by Riffo et al. [6]. It evaluates the textual, pragmatic and critical aspects involved in reading comprehension. Scores were transformed into percentiles, based on raw score performance.

Confidence in performance judgments were collected globally (before and after taking the test) and locally (item by item) by asking students to answer a question about their confidence in answering the item correctly. The responses were subsequently coded as 0 for incorrect and 1 for correct. Correct responses were summed for each participant and linearly transformed to percentiles.

The Meta-Understanding Inventory (MI), initially developed by Soto et al. [9], explores individuals’ metacognitive dimensions. All elements of cognition knowledge were transformed into percentiles. The Motivations for Reading Questionnaire (MRQ), developed by Wigfield et al. [10], measures the main components of reading motivation in its theoretical components. Student scores were transformed into percentiles.

A think-aloud protocol was employed to infer the strategies used by the participants. Each participant’s think-aloud was recorded in audio and video for subsequent transcription and coding of the presence of each strategy and the number of times these were repeated. These scores were also expressed as percentiles.

Results

Results demonstrated that both students with ASD and their typically developing peers showed expected performance in the comprehension test. However, there were statistically significant differences between both groups in the pragmatic dimension proposed by the Lectum test, in which the ASD group (M = 25.12, SD = 24.77) manifested a lower mean score compared to the typical group (M = 46.02, SD = 25.35), F(1,80) = 14.26, p < .001, η² = .151. This suggest that students with ASD have limitations in recognizing the characters, their social, cultural, and historical context, and the social function that the text presents according to their gender and, therefore, build the coherence of the text.

Regarding metacognitive monitoring, readers with ASD and typical readers exhibited better monitoring accuracy in the retrospective global judgments (after the task; ASD: M = 54.74, SD = 27.30; typical: M = 51.49, SD = 24.16) than in the prospective judgments (before the task; ASD: M = 71.15, SD = 24.83; typical: M = 69.02, SD = 24.11), F(1,80) = 69.70, p < .001, η² = .466; however, readers with ASD were less accurate in their metacognitive monitoring, although that difference was not statistically significant or meaningful, p = .78, η² = .001. In addition, a series of stepwise ordinary least squares regressions showed similar predictive patterns for both groups. More specifically, reading comprehension performance was only predicted by the raw frequencies of cell a and cell c of local monitoring accuracy (see Schraw et al., [11], for a comprehensive explanation of the 2 x 2 performance judgment-actual performance array). For the typical group, the omnibus model was practically and statistically significant, F(4,36) = 62.58, p < .001, R²_adjusted = .860; the same was the case for the ASD group, F(4,36) = 34.60, p < .001, R²_adjusted = .771. Cell a (correct performance judged to be correct) positively predicted reading comprehension (ASD group: b = 4.57 [CI_95% = 3.28, 5.86]; β = .97, p < .001; typical group: b = 4.89 [CI_95% = 3.79, 5.99]; β = .76, p < .001) whereas cell c (incorrect performance judged to be correct, also known as overconfidence or an illusion of knowing) negatively predicted (ASD group: b = 2.84 [CI_95% = .29, 5.41]; β = .22, p = .03; typical group: b = 5.00 [CI_95% = 2.64, 7.36]; β = .33, p < .001) reading comprehension.

Regarding metacognitive knowledge, planning (b = .60 [CI_95% = .27, .94]; β = .50, p = .001) positively predicted reading comprehension for the ASD group, F(1,39) = 13.26, p = .001, R²_adjusted = .235, whereas reading process evaluation (b = .51 [CI_95% = .16, .86]; β = .43, p = .005), F(1,39) = 8.70, p = .005, R²_adjusted = .161, positively predicted reading comprehension for the typical group. In reading motivation, reading efficacy (b = .63 [CI_95% = .22, 1.05]; β = .44, p = .004), F(1,39) = 9.42, p = .004, R²_adjusted = .174, positively predicted reading comprehension for the ASD group, meaning that this group has beliefs about reading adequately. For the typical group, self-efficacy (b = .61 [CI_95% = .32, .91]; β = .56, p < .001), F(1,39) = 17.40, p < .001, R²_adjusted = .291, positively predicted reading comprehension, meaning that typical readers strive for satisfaction for mastering complex ideas in a text and, like the ASD group, present beliefs for reading adequately.

With respect to strategies, for the ASD group, bridging inferences (b = 2.71 [CI_95% = .32, 5.09]; β = .32, p = .027), elaborative inferences (b = 1.12 [CI_95% = .15, 2.09]; β = .32, p = .025), and paraphrasing (b = .27 [CI_95% = .02, .52]; β = .28, p = .037) positively predicted reading comprehension, F(3,37) = 7.27, p = .001, R²_adjusted = .320. For the typical group, the total score in the use of all strategies (b = 2.88 [CI_95% = 1.98, 3.78]; β = .66, p < .001) and elaborative inferences (b = .82 [CI_95% = .25, 1.40]; β = .29, p = .006) positively predicted reading comprehension, F(2,38) = 45.34, p < .001, R²_adjusted = .689.

Discussion and Conclusion

These findings allow us to conclude that people with ASD achieve normal performance in the reading comprehension test; however, in the pragmatic aspects of reading comprehension, as measured by Lectum, they evince lower performance. In addition, the results reveal that metacognitive elements, motivation for reading, and the use of comprehension strategies significantly predicted reading performance in this group of students; nevertheless, not all the variables present a significant effect. In this sense, there is a greater tendency to use a type of low-level strategies, which help to maintain local coherence (paraphrasing, bridging inference). There is plausibly a bias in the reading of students with ADS around the flexibility factor, which decreases their ability to process certain types of information (affecting the integration process). This becomes more evident in the processing of pragmatic situations where, despite the strategies used, they tend to lose control in reading efficiency. This is congruent with extant research [7,12], and it underscores the need to tailor educational interventions to exceptional students with learning disabilities, such as ASD.

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