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Discussion | hypoparathyroidism, normocalcemia, hypercalcemia, PaTHway, hypocalcemia | DISEASE, HYPOPARATHYROIDISM, HYPERCALCEMIA, SECONDARY, ADVERSE EVENT, HYPOCALCEMIA | In this randomized trial of women and men with chronic hypoparathyroidism, PTH replacement therapy with TransCon PTH robustly improved and maintained mean serum calcium levels in the normal range at all study visits, while allowing independence from conventional therapy. Treatment with TransCon PTH additionally resulted in significant improvement in physical functioning and well‐being, as well as potential longer‐term benefits evident in the normalization of urinary calcium excretion. TransCon PTH treatment was safe and well‐tolerated, with no participants discontinuing therapy because of a related adverse event. Unique to this trial was the ability to titrate the dose of TransCon PTH offering an individualized approach to improve treatment outcomes.Significantly more participants treated with TransCon PTH (79%, In the phase 2 PaTH Forward trial, TransCon PTH was associated with normalization of renal absorption of filtered calcium from baseline (415 mg/24 h) to week 26 (178 mg/24 h).Individuals with hypoparathyroidism often experience physical and cognitive symptoms that impact multiple dimensions of health and well‐being that persist despite conventional therapy and improvements in serum calcium.TransCon PTH was well‐tolerated with a safety profile as expected. Most AEs were mild or moderate in severity and no TRAEs led to withdrawal from the trial. There was a numerically greater incidence of hypercalcemia with TransCon PTH within the first 3 months of treatment and a consistently greater incidence of hypocalcemia with placebo throughout the trial. The majority of participants (57 of 61) receiving TransCon PTH remained on a stable dose of study drug for a minimum of 4 weeks before assessment of the primary endpoint, supporting a durable treatment effect.Potential limitations of this trial merit consideration. Real‐time measurement of serum calcium was not available, and therefore, symptoms suggestive of calcium abnormalities could not be universally confirmed with laboratory studies before treatment with PRN conventional therapy. Participants and investigators were blinded to the allocation of study drug but were aware of calcium and active vitamin D doses for safety reasons. The substantial reduction in conventional therapy in participants treated with TransCon PTH has the potential for a degree of functional unblinding and may have contributed to changes in patient‐reported outcomes. Evaluation of long‐term effects of treatment and event‐driven evaluation of end‐organ outcomes were limited by trial duration, though data from the ongoing open‐label extensions of the PaTH Forward and PaTHway trials will permit further assessment.The participant population of the PaTHway trial is consistent with previous clinical trials in hypoparathyroidism and representative of previously reported cohorts of this disease, supporting the generalizability of these results to the broader population of adults with chronic hypoparathyroidism.The PaTHway trial met all primary and key secondary endpoints with statistically significant differences from placebo. In this randomized trial of adults with hypoparathyroidism dependent on conventional therapy, the ability to maintain normocalcemia while gaining independence from active vitamin D and elemental calcium (>600 mg/d) was significantly greater among the participants who received TransCon PTH compared with those receiving placebo. TransCon PTH treatment was well‐tolerated, normalized mean 24‐hour urine calcium excretion, and led to improvements in HRQoL and hypoparathyroidism‐related symptoms, functioning, and well‐being. The results of the PaTHway trial both confirm and extend findings from initial reports of the efficacy of treatment with TransCon PTH in restoring physiological functions of PTH in individuals with chronic hypoparathyroidism. | PMC10099823 |
Disclosures | LGA, CM, LCH, CTS | AAK: Research investigator for Alexion, Amgen, Ascendis, Chugai, Radius, Takeda, and Ultragenyx. MRR: Research investigator for Ascendis Pharma Inc. PS: Research investigator for Ascendis Pharma A/S. TJV: Advisory board member for Takeda; receives consulting fees from Ascendis Pharma Inc.; and research investigator for Ascendis Pharma Inc. DMS: Advisory board member for Amolyt; receives consulting fees from Takeda; and research investigator for Ascendis Pharma Inc. CG: Advisory board member for Novo Nordisk; grant recipient from Novo Nordisk; and research investigator for Shire and Ascendis Pharma Inc. AP: Research investigator for Ascendis Pharma A/S. CM: Research investigator for Ascendis Pharma A/S. BLC: Advisory board member for Takeda, Shire, PARADIGHM Registry Steering Committee, Ascendis Pharma Inc; grant recipient from Takeda, Shire, Chugai, and Ascendis Pharma Inc.; and research investigator for Ascendis Pharma Inc. LGA: Research investigator for Ascendis Pharma Inc and Takeda; and speaker for Abbvie and Clarus. LCH: Advisory board member for Amgen, Kiowa Kirin International, and UCB. LK: Advisory board member for Alexion; research investigator for Ascendis Pharma Inc; and speaker for Radius, Amgen, and Alexion. SP, XA, WE, ARS, JU, CTS, and ADS: Employee of Ascendis Pharma Inc. LR: Advisory board member for Takeda and Amolyt; grant recipient from Kyowa Kirin and Takeda; and research investigator for Ascendis Pharma A/S, Takeda, and Kyowa Kirin. | PMC10099823 |
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Author Contributions | PMC10099823 |
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Supporting information |
Click here for additional data file. | PMC10099823 |
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Acknowledgments | BONE DISEASES | This work was supported by Ascendis Pharma Bone Diseases A/S, Hellerup, Denmark. The ClinicalTrials.gov number is NCT04009291. The authors thank the trial participants and their families, investigators, and the trial staff. Medical writing support was provided by Kristin Hirahatake, PhD, and Nayna Sanathara, PhD, of Ascendis Pharma Inc. | PMC10099823 |
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Data Availability Statement | The data sets generated during and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request. | PMC10099823 |
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References | PMC10099823 |
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Abstract | PMC10467537 |
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Introduction/Objective | DISEASE, ANKYLOSING SPONDYLITIS | Newly created systems called hippotherapy simulators (HS) mimic the primitive movements of a live horse. As they are new systems, research examining their usefulness has been well received. The aim of this study is to research the effects of HS on disease activity, quality of life and muscle strength in patients with ankylosing spondylitis (AS). | PMC10467537 |
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Methods | ANKYLOSING SPONDYLITIS, DISEASE | In a prospective, assessor-blinded, block-randomized trial, 48 AS patients were randomly assigned in a 1:1 ratio to receive either HS or conventional home (CH) exercise therapy. All Participants received 48 sessions, that is 4 sessions a week for 12 consecutive weeks. The primary outcome measures included the quadriceps muscle strength, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI) and Ankylosing Spondylitis Quality of Life Scale (ASQoL). | PMC10467537 |
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Results | Both groups demonstrated significant improvement in BASDAI, BASFI, BASMI, ASQoL and muscle strength scores compared to the baseline ( | PMC10467537 |
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Conclusions | DISEASE | The results of this clinical trial of HS exercises for AS patients indicate a positive effect on disease activity, quality of life and muscle strength. Therefore, horse-riding simulator exercises can be used as an alternative method for the management of individuals with AS. | PMC10467537 |
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HIGHLIGHTS | ankylosing | DISEASE, ANKYLOSING SPONDYLITIS, CHRONIC INFLAMMATORY DISEASE |
Hippotherapy simulator exercises indicate a positive effect on disease activity, functionality and muscle strength in people with ankylosing spondylitisFor people with ankylosing spondylitis, hippotherapy simulator exercises are a safe workout for the spine that uses the core muscles.For people with ankylosing spondylitis, the hippotherapy simulator technique can be recommended as a long-lasting and affordable fitness program in the near future.To determine the efficacy of hippotherapy simulation exercise on other systemic chronic inflammatory disease future research are needed. | PMC10467537 |
Keywords | PMC10467537 |
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Clinical trials number: | PMC10467537 |
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Introduction | pain | DISEASE, ANKYLOSING SPONDYLITIS | People with Ankylosing Spondylitis (AS) experience joint stiffness and pain that mainly affects the spine, hips and shoulders [Horseback riding is recommended as a form of exercise as it has been shown to offer therapeutic advantages [The aim of this study is to research the effects of HS on disease activity, quality of life and muscle strength in adults with AS. Therefore, the null hypothesis of this study states that exercises with HS will have no effect on disease activity, quality of life and muscle strength in adults with AS. | PMC10467537 |
Patients and the method | PMC10467537 |
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Design and participants | heart, kidney and respiratory disease, word of mouth, necrosis | RECRUITMENT, NECROSIS | This prospective study was conducted as a randomized trial with parallel groups in a single-center. The setting of this quantitative study was the outpatient clinic of the physical medicine and rehabilitation department of a university hospital (University of Usak (Turkey)) between September 2020 and February 2022.After the trial was approved by the Ethical Committee of Usak University (ID:38824465-020), prospectively registered on Prior to a participant’s recruitment, all subjects completed informed consent forms. Also, as a part of the consent process all volunteers were told that they could quit the study at any time as part of the consent process.Participants were recruited through the announcements on social media and newsletter from the local AS patient associations and by word of mouth among the outpatient clinic staff of the rheumatology department. Individuals were recruited and enrolled based on the following inclusion criteria: confirmed diagnosis of AS by a rheumatologist according to the modified New York diagnostic criteria, diagnosed as AS at least for two years, age 18 to 50 years, regular use of disease-modifying anti-rheumatic drugs (anti-tumor necrosis factor (TNF) agents, sulfasalazine) at a stable dosage for at least twelve weeks. Patients were excluded if they had a regular exercise habit (totaling a minimum of 150 min of moderate exercise each week) during the previous six months, or in case of the presence of comorbid conditions including severe heart, kidney and respiratory disease, also, any problems that may prevent exercising (mental health, orthopedic, and neurological). The dropout criteria for this study were serious dosage changes in regular medication or a new treatment strategy during the study period, and continuity to exercise sessions of less than 85% (see Study flow diagram. | PMC10467537 |
Randomization and blinding | Participants who met the inclusion criteria were randomized to HS or conventional home (CH) exercise groups. A statistician blinded to the study prepared the computerized random allocation sequence with different block sizes. Furthermore, to ensure that gender and age were similarly represented, random assignment to the intervention arms was stratified according to these variables.There were three measurement periods: the baseline, after the interventions (12th week), and the 24th week long-term follow-up (following the removal of interventions). So, the same physiotherapist (an outcome assessor) who assesses the patient status and outcome measures was blinded to study protocols. Baseline and follow-up assessments lasted between 45 and 60 min. | PMC10467537 |
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Interventions | ®, abduction, ’ | SEMI, ANKYLOSING SPONDYLITIS, STRETCHES | Participants in both exercise groups received 48 exercise sessions (40 min each), that is 4 sessions a week for twelve consecutive weeks. In both types of exercise, each session consisted of a five-minute warm-up, including side lunges, side stepping, half squat, biceps, triceps and deltoid warm-up exercises, and self-range of motion exercises for the cervical, thoracic and lumbar spine. In addition, 5 min of static stretches (including ‘downward facing dog’, ‘seated straddle’, ‘cat-cow’, ‘standing calf stretch’ and ‘upper trapezius stretch’ positions) were performed in both groups at the end of the exercise.Patients in the HS exercise group used the Dragon Hippotherapy Simulator (Code TA-022) as gym equipment and performed their exercise sessions in the gymnasium of XXX University Hospital. An experienced physiatrist (AYK) supervised the sessions to ensure that the patients performed the exercises correctly. The Dragon was built for indoor use and has a three-phase motor to mimic the three-dimensional movements of a live horse (up and down, forward and backward, and left to right). Participants sit in a leather-covered saddle and hold on to the saddle’s horn-like handles. Sitting in the simulator, the participant’s feet in the stirrups are in dorsiflexion, both knees and hips are in semiflexion and the hip joint is in semi abduction and external rotation. While the device was in motion, participants were verbally reminded to keep their head upright and look forward and to maintain correct posture (see (a and b) A Patient’s position for the horse stimulation exercise using the Dragon® hippotherapy simulator.Muscle groups that are active to ensure correct posture and balance are shown while the simulator is running.Position of patients with ankylosing spondylitis for the microFET® 2 dynamometer knee-extensor assessment.The conventional home exercise program consisted of a warm-up (mentioned above), body weight strength training, balance exercises, and static stretching (mentioned above), as demonstrated by the physiatrist (AYK) at the beginning of the study period. During the study period, participants were encouraged to participate and their continuity was checked by phone calls within 14 days. In addition, all patients received an exercise manual booklet and exercise diary.> Low- or moderate-intensity bodyweight exercise routines were physical tasks performed in the current study. The first exercise consisted of 6–8 knee or elevated push-ups, followed by 8–12 assisted bodyweight squats, 8–12 walking or jumping jacks, and finally 8–12 assisted lunges. The participants then performed 8–12 repetitions of leg drops, scissor kicks, and chin tucks (with towel support) in the prone position. The rest was allowed between movements, but the participants were required to complete each set of each exercise before starting a new round.>Simple, enjoyable and safe balance exercises were selected for people with AS to learn. Sessions began with a standing march and 3-way kicks for 20–30 s, followed by a one-leg stand (supported if necessary) for up to 30 s. Finally, heel-to-toe standing or walking was performed for up to 30 s. A set of 3 repetitions was performed. | PMC10467537 |
Outcome measurements | Disability, quadriceps muscle, fatigue | DISEASE, DISEASE, ANKYLOSING SPONDYLITIS | For a comprehensive analysis, outcome measures were chosen to document changes in muscle strength, disease activity, spinal mobility and quality of life across different components of the International Classification of Functioning, Disability and Health, including activity, body structure and function. Primary outcomes included quadriceps muscle strength, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI) and Ankylosing Spondylitis Quality of Life Scale (ASQoL).Patients were evaluated by an experienced physiotherapist (the evaluator was blinded to study design and group allocation) at baseline, post-intervention and after 6 months of follow-up. Measurements were taken at the same time of day (10:00 am) and measured in order (muscle test, BASDAI, BASFI, BASMI and ASQoL) in the same room. The physiotherapist allowed sufficient rest time between tests to avoid patient fatigue. | PMC10467537 |
Quadriceps muscle strength testing | Quadriceps muscle strength was tested with a microFET-2 dynamometer. Reliability and quantifiable force evaluation tests (Hogan Health Industries, Inc., UT, USA) were performed with this portable (wireless) handheld dynamometer [The subject was seated in an upright position with arms folded across the chest and no lumbar support. A small gap was left between the back of the knees and the chair and the knees were positioned at the same height as the hips (see | PMC10467537 |
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BASDAI | tenderness, morning stiffness, fatigue, pain | DISEASE, THIGH DISEASE | The patient was asked to answer six questions regarding the five main symptoms of AS (fatigue, spinal pain, joint pain, tenderness, pain intensity and morning stiffness) over the past week. These self-administered questions are on a 0–10 scale and the resulting score of 0 to 50 is divided by five to obtain the final BASDAI score (0–10). Low BASDAI scores indicate low disease activity and good disease control, while high scores indicate high disease activity and poor disease control [ | PMC10467537 |
BASFI | Ten questions comprising the BASFI were asked to assess patients’ activities related to their functional and anatomical limitations. A ten-point visual analog scale (zero being ‘easy’ and ten being ‘impossible’) was used to score each question, and the BASFI score (a value between 0 and 10) was obtained from the average of the ten scales. Higher values are indicative of severe impairment [ | PMC10467537 |
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BASMI | hip mobility (intermalleolar distance) | The BASMI was used to assess the effect of exercise interventions on spinal mobility. This scale ranges from 0 to 10, with lower scores indicating less mobility limitation and 10 indicating very severe limitation. Four measures of spinal mobility (tragus-to-wall distance, cervical rotation, lumbar lateral flexion and modified Schober’s test) and one measure of hip mobility (intermalleolar distance) were applied. The total score was calculated using the BASMI-10 scoring system [ | PMC10467537 |
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ASQoL | pain | ANKYLOSING SPONDYLITIS | The 18-item Ankylosing Spondylitis Quality of Life (ASQoL) instrument was used as a reliable tool to assess the impact of exercise interventions on pain, mood, sleep, motivation and ability to cope with daily tasks, relationships, self-image and self-esteem. Higher scores on these Yes/No questions indicate poorer quality of life in AS patients [ | PMC10467537 |
Sample size calculation | The number of participants included in this study was determined based on quadriceps muscle test data from a previously published study. According to the results of Ogut et al. the mean muscle strength before treatment was 40.6 Nm with a standard deviation of 6.5. The mean muscle strength after treatment was 44.8 Nm. The sample size calculation was based on a power of 80% (β 0.2), a dropout rate of 25% and a statistical significance (α = 0.05) of 95% ( | PMC10467537 |
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Statistical analysis | ® | Data analysis was performed using IBM® SPSS® statistics 17.0 software (SPSS Inc. Released 2008. SPSS Statistics for Windows, Version 17.0. Chicago). The normal distribution of variables was examined using the Kolmogorov-Smirnov test, which was suitable for our sample sizes. Median, minimum and maximum values and percentages were used to present quantitative data. Changes from baseline to follow-up examinations are presented descriptively as trend directions in the outcome response. Change within group was assessed by calculating the change in variables (follow-up value minus baseline value) and reported as median difference. Student’s t-test was used to compare baseline demographic and clinical characteristics between groups and descriptive statistics were calculated for demographic data. Cohen’s d coefficient was used to calculate the effect size for change in each group (mean SD of differences). Effect sizes were divided into three categories: small ‘0.20–0.49’, medium ‘0.50–0.80’ and high ‘>0.8’. A P-value less than 0.05 was considered statistically significant. | PMC10467537 |
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Results | ADVERSE EFFECTS, ANKYLOSING SPONDYLITIS, DISEASE | Forty-eight people with AS participated in this study. Six patients dropped out due to inability to participate in exercise sessions (The mean age for the entire cohort was 34.9 years and 64.2% of the cohort was male. The groups were similar and there was no significant difference between the two groups in terms of demographic/clinical characteristics and baseline physical examination findings (Demographics and characteristics of participants (HS: Hippotherapy simulation exercise; CH: Conventional home exercise; SD: Standard deviation; BMI: body mass index (kg/mNo serious or mild adverse effects were noted in either group. Only one patient experienced transient discomfort immediately after the first two sessions of HS exercise. However, this patient tolerated the exercise well and no medical intervention was required.Baseline BASDAI, BASFI, BASMI, ASQoL and muscle strength scores were similar between the two groups (Within-group and between group comparisons of outcomes.BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; BASMI: Bath Ankylosing Spondylitis Metrology Index; ASQoL: Ankylosing Spondylitis Quality of Life Scale N: newton; HS: Hippotherapy simulation exercise; CH: Conventional home exercise; SD: Standard deviation. | PMC10467537 |
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Discussion | ’ differing disease severity, exercise frequency, pain | ADVERSE EVENTS, DISEASE | This study demonstrated that 48 sessions of hippotherapy simulation workouts significantly improved functionality, muscle strength and quality of life in individuals with AS leading a sedentary lifestyle. Comparing the treatment approaches, daily activity scores, functionality and spinal mobility showed a statistically better improvement in the HS group at week 12. All patients tolerated the planned exercise programs and no adverse events were recorded during the training sessions in either group. Nevertheless, this prospective study did not show improvement in any study outcome at 6-month follow-up.According to the analytical assessment of Hilliere et al. HS improves the physical and mental skills of elderly patients [Potential reasons for heterogeneity in exercise trials on people with AS include participants’ differing disease severity, exercise frequency, intensity, duration and types of exercise. However, the results of systematic reviews of exercise interventions in patients with AS show a high level of consistency, suggesting mild to moderate benefits for disease activity, axial mobility, function and pain. According to a Cochrane review aimed at evaluating the benefits of exercise programs for people with AS, exercise approaches showed a reduction in disease activity with low-quality evidence compared with usual care [A few AS studies have included muscle strength training as part of the exercise program. However, in most of these studies, neither muscle strength nor other relevant physiological responses were measured [A home-based exercise approach is a simple and cost-effective treatment for AS patients. Compared to a control group, there is moderate-quality evidence that home-based or supervised individualized exercise regimens have a positive impact on various measures of spinal mobility in AS patients [Although this study provided novel and important results, some potential shortcomings should be mentioned. While acute-phase reactants, particularly erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), may be quantitative follow-up parameters that can be used to monitor AS patients, our study did not have laboratory tests to define disease activity or progression with interventions. Second, in comparing the two separate exercise regimens, the groups were given the same amount of time to exercise but not the same intensity. Therefore, future studies should compare AS patients who received HS treatment with AS patients who received supervised exercise on land or in water. Another limitation is that we can only generalize our results to individuals with AS with mild disabilities; therefore, caution should be exercised in generalizing the results. Finally, not all measures were collected because of concerns about survey overload. Future studies should include assessment of balance and core muscle activation or endurance. Cost-effectiveness and treatment satisfaction with HP are also issues that need to be investigated. | PMC10467537 |
Conclusion | DISEASE | The results of this first randomized clinical trial of HS exercises for AS patients indicate a positive effect on disease activity, quality of life and muscle strength. Thus, the social advantage of this clinical trial is the opportunity to introduce a novel recreational exercise approach for AS patients. The possibility of combining HS exercises with other types of therapy could be a new research topic in future studies. | PMC10467537 |
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Author contributions | Ender Salbaş: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Writing – original draft, Writing – review & editing.Ali Yavuz Karahan: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Writing – original draft, Writing – review & editing. | PMC10467537 |
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Ethics statement | The study was conducted in accordance with the Declaration of Helsinki, and approved by the Usak University research Ethics Committee for studies involving humans (ID: 38824465-020). This study was registered in the | PMC10467537 |
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Patient consent | Informed consent was obtained from all subjects involved in this study. Written informed consent has been obtained from the all participant to publish this paper. The individual gave his explicit written consent for photos in Figures. Written consents retained by the author might be provided to Editor on request. | PMC10467537 |
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Disclosure statement | The authors declare no conflict of interest. | PMC10467537 |
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References | PMC10467537 |
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1. Introduction | Caffeine is an adenosine ATraining, nutrition, motivation, and genetics (talent) are key factors in achieving high levels of athletic performance [Adenosine is one of the metabolites produced by dephosphorylation of the Adenosine Triphosphate (ATP) via 5-nucleotidease enzyme during the exercise [Research suggests that caffeine can block adenosine receptors, which may induce increased neurotransmitter dopamine release [Adenosine AThere seems to be inter-individual differences in response to caffeine intake among people [There is no study investigating the effect of the In addition to MPO, the hydrolytic acetylcholinesterase (AchE) enzyme is considered as an inflammatory marker [It has been shown that caffeine has anti-inflammatory effects and is able to significantly reduce the activity of MPO and AchE during exercise activity [Therefore, the aim of the present study was twofold: (1) to investigate the association of the | PMC10097079 |
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2. Materials and Methods | PMC10097079 |
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2.1. Ethics Statement | The Institutional Review Board of the Faculty of Humanities and Social Science (No. 1314796, 08.10.95) and Iran National Committee for Ethics in Biomedical Research at University of Kurdistan (IR.UOK.REC.1398.047) and the Ethics Committee of the Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency of Russia (Approval number 2017/04) approved the protocols for the research. Written informed consent was obtained from each participant. The studies were complied with the guidelines set out in the Declaration of Helsinki and ethical standards in sport and exercise science research. | PMC10097079 |
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2.2. Participants | PMC10097079 |
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2.2.1. Resistance Exercise Study | Fifteen resistance-trained Iranian men were randomly selected to participate in the randomized, double-blind, placebo-controlled study. Physical characteristics of 15 male subjects with different | PMC10097079 |
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2.2.2. Habitual Coffee Intake Study | A total of 134 Russian healthy (non-smokers), physically active (>3 training sessions per week) subjects (45 females, age 28.4 (7.1) years, height 168.0 (5.9) cm, weight 59.5 (6.1) kg; 89 males, age 31.4 (8.6) years, height 179.8 (6.2) cm, weight 80.2 (10.3) kg) participated in this study. | PMC10097079 |
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2.3. Resistance Exercise Study Design | One week before starting the experimental session, maximal strength was assessed by one Repetition Maximum (1RM) test in bench press, leg press, seated cable row, and shoulder press. Participants were asked to abstain from performing the exercise 3 days before the 1RM test and experimental sessions, and to avoid consumption of caffeine for 24 h before testing.Then, in a randomized, double-blind, placebo-controlled, and cross-over design, participants consumed 6 mg per kg bodyweight caffeine or a placebo one hour before RE. After one hour, blood samples were taken from antecubital vein of the subjects; then, they participated in 3 sets of RE to failure with 85% of 1RM, consisting of bench press, leg press, seated cable row, and shoulder press. Two minutes of rest period between sets and exercise was taken. Additional blood samples were taken from the venous vein immediately after (Post) and 15 min after RE (15 min Post). After 3 days of washout, the subjects were recalled and treated with caffeine or placebo, with a change in supplementation and placebo, under the same conditions. Then, they participated in RE under the previous conditions again. | PMC10097079 |
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2.4. Assessment of Habitual Coffee Intake | Habitual coffee intake was assessed using a dietary questionnaire administered to all participants. Responses to the questions on coffee were assigned values for frequency per week (never = 0, once per week = 1, 2–3 times per week = 3, 4–5 times per week = 5, and once or more a day = 7). | PMC10097079 |
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2.5. Biochemical Analysis | SEPARATION | After sampling, 5 mL of venous blood was used for serum separation. Serum samples were stored at −20 °C until the day of analysis. The ELISA method was used for analyzing the activity of myeloperoxidase (MPO) and acetylcholinesterase enzymes (AchE) in Iranian subjects (ELISA Kit, Eastbiopharm, Hangzhou, Zhejiang, China). | PMC10097079 |
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2.6. Genotyping | PMC10097079 |
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2.6.1. Resistance Exercise Study | After sampling, 2 mL of blood was injected in K2EDTA-containing Venoject for DNA extraction (TIANamp Genomic DNA) to study the Single-Nucleotide Polymorphism (SNP) in The thermal protocol for PCR operation consisted of step (1) the primary denaturation for 10 min at 94 °C, step (2) second denaturation for 1 min at 94 °C, step (3) annealing for 1 min at 65 °C, step (4) extension for 1 min at 72 °C (steps 2 to 4, 32 cycles), and step (5) final extension for 5 min at 72 °C.In order to verify that PCR was performed in all samples, the internal control was used, in which two primers of mitochondrial genome (namely L strand: 5′-CTCCACCATTAGCACCCAAAGC-3′ and H strand: 5′-CCTATTTGTTTATGGGGTGATG-3′) were used to produce a 250 bp fragment. All samples were run in duplicate with two negative controls. | PMC10097079 |
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2.6.2. Habitual Coffee Intake Study | Molecular genetic analysis was performed with DNA samples obtained from leukocytes (venous blood). Four ml of venous blood were collected in tubes containing EDTA (Vacuette EDTA tubes, Greiner Bio-One, Kremsmünster, Austria). DNA extraction and purification were performed using a commercial kit according to the manufacturer’s instructions (Technoclon, Moscow, Russia). HumanOmniExpressBeadChips (Illumina Inc., San Diego, CA, USA) or HumanOmni1-Quad BeadChips (Illumina, San Diego, CA, USA) were used to genotype | PMC10097079 |
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2.7. Statistical Analysis | REGRESSION | Statistical analyses were conducted using Statistical Package for the Social Sciences (SPSS) for Windows v21.0 (IBM Crop, Armonk, NY, USA) or GraphPad InStat (GraphPad Software, Inc., San Diego, CA, USA) software. A 2 × 2 × 3 general linear model repeated measures ANOVA was used to examine acetylcholinesterase and myeloperoxidase concentrations after caffeine ingestion, with genotype group (TT vs. CT/CC) as between-subjects factor and condition (caffeine vs. placebo) and sampling time (pre, post, and 15 min post) as the within-subjects factor. Multiple regression was used to assess the relationship between coffee intake and | PMC10097079 |
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3. Results | PMC10097079 |
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3.1. Association of ADORA2A Variant with Anti-Inflammatory Effects of Caffeine in Response to Intense Resistance Exercise | No significant differences were determined in age, height, weight, soft lean mass, body fat mass, percent body fat, body mass index, and basal metabolic rate between the carriers of the Repeated measures ANOVA revealed a significant genotype (TT vs. CT/CC) × time (pre, post, and 15 min post) interaction effect in caffeine condition (F = 8.36, Regarding to MPO concentration, no significant genotype (TT vs. CT/CC) × time (pre, post, and 15 min post) interaction effect in both caffeine (F = 1.55, | PMC10097079 |
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3.2. Association of ADORA2A Variant with Habitual Coffee Intake | In 134 physically active Russian individuals (TT: 22, CT: 53, CC: 59), the | PMC10097079 |
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Author Contributions | Conceptualization, M.R.R. and I.I.A.; methodology, M.R.R. and I.I.A.; formal analysis, M.R.R., E.A.S., I.I.A. and H.G.; funding acquisition, B.Ł.; investigation, M.R.R., E.A.S., A.K.L., N.A.K., E.V.G., I.I.A. and H.G.; validation, B.Ł.; writing—original draft preparation, M.R.R., I.I.A. and H.G. All authors have read and agreed to the published version of the manuscript. | PMC10097079 |
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Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of the Faculty of Humanities and Social Science (No. 1314796, 08.10.95) and Iran national committee for ethics in biomedical research at University of Kurdistan (IR.UOK.REC.1398.047), and by the Ethics Committee of Federal Research and Clinical Center of Physical-chemical Medicine of the Federal Medical and Biological Agency of Russia (Approval number 2017/04). | PMC10097079 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10097079 |
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Data Availability Statement | The data presented in this study are available on request from the corresponding authors. | PMC10097079 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC10097079 |
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References | AChE response to resistance exercise in athletes with MPO response to resistance exercise in athletes with Physical characteristics of the subjects with Values are Mean ± SD, there were no significant differences between group.Percent change of MPO and AChE levels in caffeine and placebo condition in C, caffeine group; P, placebo group. * | PMC10097079 |
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Abstract: | This article has supplementary material on the web site: | PMC10686276 |
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Objective: | GDM | GDM, GESTATIONAL DIABETES MELLITUS | We compared cognitive profile and neuropsychological performance in 9-year-old offspring of mothers who were treated with metformin or insulin for gestational diabetes mellitus (GDM). | PMC10686276 |
Methods: | calculus, GDM | GDM | A total of 172 children whose mothers were randomly assigned to receive either metformin or insulin for GDM were studied at the age of 9 years. Of these children, 127 were from Turku, Finland (63 metformin and 64 insulin), and 45 from Oulu, Finland (19 metformin and 26 insulin). Clinical and demographic background characteristics were obtained at enrolment, birth, and 9-year follow-up. Cognitive profiles were examined at age 9 years with the Wechsler Intelligence Scale for Children. Neuropsychological functions were examined with 2 subtests of the Developmental Neuropsychological Assessment test battery assessing comprehension of instructions and narrative memory, Trail Making Test assessing attention and with Behavioral Rating Inventory of Executive Functioning, including parent-rated and teacher-rated evaluations. Academic functioning was studied with reading fluency subtest of the Screening test for reading, writing, and calculus for first to sixth grades and information about educational support received at school reported by parents. | PMC10686276 |
Results: | The cognitive profiles, including indexes of verbal comprehension, perceptual reasoning, working memory, and processing speed, did not differ significantly between metformin-treated and insulin-treated groups. Significant differences were not found between the treatment groups in assessed neuropsychological functions, reading fluency, or received level of support at school. | PMC10686276 |
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Conclusion: | GDM | GDM | Cognitive and neuropsychological outcomes were similar in 9-year-old children whose mothers had either metformin or insulin treatment of GDM. | PMC10686276 |
Index terms: | hyperglycemia, GDM | GDM, HYPERGLYCEMIA, GESTATIONAL DIABETES MELLITUS | Gestational diabetes mellitus (GDM) is defined as a condition in which hyperglycemia develops and is diagnosed for the first time during pregnancy.Metformin is increasingly used in the treatment of GDM. However, metformin crosses the placenta with fetal levels similar to maternal concentrations.Mice studies have shown that male and female offspring may develop different metabolic phenotypes after similar exposure, e.g., GDM or metformin medication during pregnancy.Previously, neurodevelopment of offspring in randomized studies comparing maternal metformin or insulin treatment of GDM has been followed only until the age of 18 monthsThe aim of this study was to assess possible long-term effects of prenatal metformin exposure on cognitive and neuropsychological performance in 9-year-old children. The study subjects were children born to mothers with GDM randomized to metformin or insulin treatment. Cognitive and neuropsychological outcomes between children of metformin and insulin groups were also analyzed in subgroups by sex. The age of 9 years, just before the onset of puberty and after completing the second grade of primary school education, was considered the most appropriate age to compare the cognitive and neuropsychological variables between the offspring of the 2 treatment groups. | PMC10686276 |
METHODS | PMC10686276 |
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Study Subjects | calculus, GDM | GDM, SYNDROME, GESTATIONAL DIABETES MELLITUS | This was a prospective follow-up study in the offspring of 2 previously published Finnish randomized controlled trials with similar study designs,Participants of the 2 original randomized controlled trials and those of the 9-year follow-up study. †Of the 110 participants, who completed the original study in the metformin group in Turku, 3 offspring were excluded because 1 child had valproate syndrome, 1 child had down syndrome, and 1 child was stillborn. In the 9-year follow-up of 82 participants in the metformin group, 2 children were excluded (Swedish language), and for 2 children, a psychologist was not available for testing. ¤Of the 90 participants in the insulin group, 7 children were excluded because 1 child had attended a psychological test within less than a year, 8 children had Swedish as a school language, and for 1 child, a psychologist was not available for testing. BRIEF, Behavioral Rating Inventory of Executive Functioning; GDM, gestational diabetes mellitus; LUKILASSE, Screening test for reading, writing, and calculus for first to sixth grades; NEPSY II, developmental neuropsychological assessment test; TMT, Trail Making Test; WISC, Wechsler Intelligence Scale for Children.This 9-year follow-up study was conducted at 2 sites, Turku University Hospital in Southwest Finland and Oulu University Hospital in Northern Finland, between 2015 and 2019. Examination included measurements of growth, body composition, and blood tests for metabolism, and these results were reported previously.Written informed consent was obtained from each mother, child, and father. The assessors were blinded to the treatment allocation of the mothers. The 9-year follow-up study was registered with the Clinical Trials Registry (NCT02417090) and approved by the Ethics Committee of the Hospital District of Southwest Finland (ETMK 31/2015, April 27, 2015). | PMC10686276 |
Cognitive and Neuropsychological Assessments | Neuropsychological test battery for the purposes of this study was designed to cover essential functions of development and school performance of 9-year-old children. Neuropsychological assessments were performed in Finnish. Two psychologists and 3 final-stage psychology students under the guidance of an experienced psychologist made the assessments over a 4-year period. | PMC10686276 |
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Data Analysis | Owing to a relatively small number of children in both study groups, post hoc power analysis was performed to evaluate the reliability of the results. Assuming at least noninferiority between the study groups, the required sample sizes were calculated to attain 80% statistical power on 95% significance level with 10 points as a noninferiority margin using the observed group means and pooled SD. We chose a 10-point difference because we were interested in clinically significant difference that might affect the performance of the children. In this setup, we found that sufficient total sample size to assess noninferiority for FSIQ is n = 95 subjects and for PRI n = 216 subjects. This analysis was performed using R: a language and environment for statistical computing, version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria) and epiR package, version 2.0.57 (Stevenson et al.).The Kolmogorov-Smirnov test was used to analyze whether the variables were normally distributed, and the Shapiro-Wilk test was used to test the normality of the subgroups of boys and girls (n < 50). Continuous variables are described using means, SDs or medians, and interquartile ranges (IQR). Categorical variables are described using frequencies and percentages. Between-group comparisons in continuous variables were performed using Student's | PMC10686276 |
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RESULTS | PMC10686276 |
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Study Subjects | GDM | GDM, HYPOGLYCEMIA, GESTATIONAL DIABETES MELLITUS | A total of 172 children (82 in the metformin group and 90 in the insulin group) were followed up at 9 years. The means or medians of cognitive development, neuropsychological performance, and academic functioning were similar in offspring assessed in the 2 study sites (Turku n = 127, Oulu n = 45), which allowed further analysis to be made as a single group. The results of neuropsychological assessments were eligible in 159 participants, which is 51% of the 311 children in the original cohort and 77 (48%) of these belonged to the metformin group and 82 (52%) belonged to the insulin group (Fig. Pregnancy, Neonatal, and 9-Yr Follow-Up Characteristics of the Participants in the 9-Yr Follow-Up StudyPsychological assessments were performed in 159 participants. Comparison between the groups treated with metformin or insulin for GDM.Data are expressed as mean ± SD, median (IQR), or n (%). The BMI, body mass index; GDM, gestational diabetes mellitus; IQR, interquartile ranges.No significant differences between the participants and nonparticipants of the 9-year follow-up study were found in maternal baseline characteristics of pregnancy, i.e., pre-pregnancy body mass index (BMI), glycemic status, smoking habits, distribution of metformin and insulin treatments, duration of medication, and gestational weeks at delivery. The same was true in neonatal measures, i.e., birth weight, umbilical artery pH, Apgar score, need for IV glucose for hypoglycemia, and sex distribution of the children within the groups (Table S1, Supplemental Digital Content 1, | PMC10686276 |
Cognitive Development at the Age of 9 Years | calculus, GDM | GDM, GESTATIONAL DIABETES MELLITUS | The results of Full-Scale Intelligence Quotient, Verbal Comprehension Index, PRI, Working Memory Index, and Processing Speed Index between metformin and insulin groups were similar (Table Cognitive Development, Neuropsychological Performance, and Academic Functioning at the Age of 9 yrPsychological assessments were performed in 159 participants. Comparison between the offspring of the mothers treated with metformin or insulin for GDM.Data are expressed as mean ± SD, median (IQR) or n (%). The Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV).Two subtests of the Developmental Neuropsychological Assessment (NEPSY-II) test battery and TMT.One subtest of the Screening test for reading, writing, and calculus for first to sixth grades (LUKILASSE) and information about received support at school.GDM, gestational diabetes mellitus; IQR, interquartile ranges; TMT, Trail Making Test. | PMC10686276 |
Neuropsychological and Academic Functions at the Age of 9 Years | GDM, GESTATIONAL DIABETES MELLITUS | The results of the 2 subtests of NEPSY II, TMT A-time and B-time, and reading fluency test by LUKILASSE were similar in the children of the metformin and insulin groups (Table Executive Functioning in Daily Life at the Age of 9 yr as Assessed by the Teacher and ParentMedians of BRIEF indexes and proportion of children who had clinically significant problems (scores above 64) in BRIEF at school or at home. Comparison between the offspring of the mothers treated with metformin or insulin for GDM.Data are expressed as median (IQR) or n (%). Scores above 64 are used to indicate clinically significant problems. The Mann-Whitney BRIEF, Behavior Rating Inventory of Executive Function; GDM, gestational diabetes mellitus; IQR, interquartile ranges. | PMC10686276 |
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DISCUSSION | cognitive and neuropsychological difficulties, fifty-nine 9-year-old, GDM, PCOS | GDM, POLYCYSTIC OVARY SYNDROME (PCOS) | In this follow-up study, which comprised one hundred fifty-nine 9-year-old children born to mothers with GDM, we found no statistically significant differences in cognitive or neuropsychological outcomes between the offspring of mothers who were treated with either metformin or insulin.It has been shown that metformin crosses the placentaTo our knowledge, this is the first report on the long-term cognitive and neuropsychological outcomes of children born to mothers with either metformin or insulin treatment of GDM. To date, in addition to previous studies of this cohort,Based on previous results, it seems that fetal exposure of metformin does not affect the motor, social, behavioral, linguistic, and cognitive development of children compared with insulin treatment, when examining children before school age. Mild cognitive and neuropsychological difficulties might become evident within age and increasing demands during school years. However, in this study, neurocognitive outcomes were similar in 9-year-old children between the metformin and insulin groups. The results of this study are in line with these studies and support the hypothesis of the safety of the antenatal metformin treatment of GDM for a child's development.It is important to observe that when metformin is used to treat polycystic ovary syndrome (PCOS), it is started during first trimester and may be continued throughout the pregnancy. Thus, possible long-term effects of metformin on offspring cognitive development might be found more likely in studies of pregnancies with PCOS mothers. As opposed to PCOS pregnancies, medication in GDM is usually started during the second or third trimester. However, in a Norwegian follow-up study of mothers with PCOS randomized to metformin or placebo treatment from the first trimester, the mean FIQ was similar in offspring aged 5 to 14 years (n = 93) in the metformin and placebo groups.A major strength of this study is that the 9-year-old offspring well represent the original cohort, which allows valid comparisons between the treatment groups. Moreover, the baseline data were similar between the 9-year-old study participants and the group of nonparticipants and between the 2 study sites. Currently, this follow-up cohort of one hundred fifty-nine 9-year-old offspring whose mothers received either metformin or insulin treatment of GDM is the largest published cohort comparing long-term effects of the medication on the cognitive and neuropsychological profiles of offspring. We consider the participation rate of 51% to be satisfactory, taking into account the long period of 9 years between birth and follow-up. In addition, neuropsychological assessment covered clinically essential functions of 9-year-old children and reflect the overall picture of their neurocognitive outcome. There were some limitations in this study. First, the neuropsychological assessments were performed by 5 psychologists or final-stage psychology students, although no differences in test score medians between the psychologists were found. Second, narrative memory test (NEPSY II) results were lower than average in both medication groups. This might be related to the ceiling effect further compounded by the exhaustion from prolonged examinations. Third, the children were examined at the age of 9 years, which led to a situation in which the studied children were in different grade levels, which might have affected the level of received educational support. Fourth, the suboptimal follow-up rate may have led to some potential differences not being detected between the treatment groups, and based on post hoc power analysis regarding FSIQ, the size of this follow-up cohort does not have power to find small differences between the groups. However, a large (10-point) difference in FSIQ could be excluded on the basis of our noninferiority power calculation.In conclusion, in this follow-up study of 9-year-old offspring of mothers with GDM randomized to metformin or insulin treatment during pregnancy, we found that metformin did not adversely affect either offspring's neurocognitive outcomes assessed by standardized tests or executive function assessed by teachers and parents. These results could obtain further confirmation by performing a follow-up study of this cohort at the end of the basic education at the age of 16 years. | PMC10686276 |
Supplementary Material | PMC10686276 |
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ACKNOWLEDGMENTS | Diabetes | DIABETES | The authors acknowledge Tommi Kauko for statistical advice and support. The authors especially thank study nurse Ulla Torkko and study nurse Tiina Latva-aho for organizing the study visits. The authors acknowledge psychologist Annarilla Ahtola, Ph.D., who was important in designing cognitive and neuropsychological assessments in this study; she sadly passed away in April 2021. The authors also acknowledge the expert work of the five psychologists who performed the psychological assessments for the children. Finally, thanks are due to all the children and parents who agreed to take part in this study.Supported by the Diabetes Research Foundation, Finland; the Finnish Foundation for Pediatric Research; Special Governmental Grants for Health Sciences (Turku University Hospital and Oulu University Hospital, Finland); Yrjö Jahnsson Foundation, Finland, and the Turku University Hospital Research Foundation, Finland.The authors declare no conflict of interest.Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site ( | PMC10686276 |
REFERENCES | PMC10686276 |
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Background: | bloating, Gut microbiome dysbiosis | Gut microbiome dysbiosis is a major cause of abdominal gas, bloating, and distension. | PMC9982755 |
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Methods: | bloating | Multicenter, randomized, double-blind, placebo-controlled study at hospitals in southern India. Seventy adults with functional gas and bloating with a gastrointestinal symptom rating scale (GSRS) indigestion score ≥ 5 were randomized to receive | PMC9982755 |
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Results: | Two participants from each group withdrew from the study and 66 participants (n = 33 in each group) completed the study. The GSRS indigestion scores changed significantly ( | PMC9982755 |
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1. Introduction | pelvic floor dysfunction, bloating, dyspepsia, abnormal intestinal gas transit, Functional bowel disorders, SIBO, IBS, Abdominal bloating, constipation, FBD | HYPERSENSITIVITY, SMALL INTESTINAL BACTERIAL OVERGROWTH | Functional bowel disorders (FBD) are highly prevalent, affecting all facets of society globally. They reduce people’s quality of life and have a negative impact on the global health care system.Although the etiology of bloating and distension is not well understood, small intestinal bacterial overgrowth (SIBO), gut microbiota alterations, intolerance to food/carbohydrates, visceral hypersensitivity, abnormal intestinal gas transit, and gas evacuation are a few common triggers of bloating.Abdominal bloating can also result from IBS, functional dyspepsia, constipation, and pelvic floor dysfunction. Diet modification, antibiotics, prokinetic agents, probiotics, antispasmodics, and neuromodulators are therapeutic options for bloating and distension.Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” ‘.The spores of The probiotic strains belonging to the same species are known to vary in their properties due to differences in their genotypic and phenotypic characteristics,The present study evaluated the efficacy of | PMC9982755 |
2. Materials and methods | PMC9982755 |
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2.2. Gastrointestinal symptom rating scale | nausea, loose stools, flatulence, heartburn, Dyspepsia, burping, Abdominal Pain, Diarrhea, constipation, Abdominal pain, borborygmi, gastrointestinal symptom rating scale (GSRS), gastric hunger pain | GI DISORDERS, SYNDROME, REFLUX | The gastrointestinal symptom rating scale (GSRS) is a 15-item questionnaire to assess the common symptoms associated with GI disorders. GSRS utilizes a 7-level Likert scale (0–6) depending on the intensity and frequency of GI symptoms experienced during the previous week. It is divided into 5 subscales. Abdominal pain, gastric hunger pain, and nausea scores are grouped under “Abdominal Pain.” Reflux, heartburn, and regurgitation scores are included in the Reflux or “Dyspepsia syndrome.” Abdominal distension, borborygmi, burping, and flatulence are included under the “Indigestion syndrome.” “Diarrhea” is evaluated based on the increased frequency of evacuation, loose stools, urgent need to defecate, and constipation by difficulty in defecating. | PMC9982755 |
2.3. Ethics and study design | The trial was conducted as a prospective, randomized, double-blind, placebo-controlled at 2 investigative sites in Bangalore (MS Ramaiah Medical College and Hospitals and Santosh Hospital) between August 2019 and March 2021. The Institutional Ethics Committees of both sites approved the study. Written informed consent was taken from all the subjects before enrollment in the study. The trial was conducted per the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice, and applicable local regulations and was registered prospectively with the clinical trial registry of India with the registration number clinical trial registry of India/2019/06/019617. | PMC9982755 |
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2.4. Sample size | The study statistician calculated the sample size based on earlier studies using a power of 80% and an alpha significance of 0.05, and correlation of 0.32, the required total sample size was calculated to be 60 for evaluation. Considering a 15% drop out rate, 70 participants were recruited and randomized in a 1:1 ratio between | PMC9982755 |
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2.5. Inclusion and exclusion criteria | bloating, dyspepsia, ulcerative colitis, IBS, postprandial distress syndrome, constipation, abdominal bloating/distension, ; active psychiatric, gastrointestinal disorders, abdominal bloating | LACTOSE INTOLERANCE, POSTPRANDIAL DISTRESS SYNDROME, ULCERATIVE COLITIS, CROHN DISEASE, FUNCTIONAL DIARRHEA, FUNCTIONAL GASTROINTESTINAL DISORDER, FUNCTIONAL CONSTIPATION, GASTROINTESTINAL DISORDERS | The study included adult (18–65-year-old) male and female participants experiencing abdominal discomfort, gas, bloating, and distension symptoms. The enrolled subjects fulfilled Rome IV C4 diagnostic criteria for functional abdominal bloating/distension. Rome IV C4 diagnostic criteria consist of recurrent bloating and/or distention occurring at least 1 day per week and a predominance of abdominal bloating and distention over other symptoms in the absence of IBS, functional constipation, functional diarrhea, or postprandial distress syndrome. As per the Rome IV criteria, these symptoms should be present for at least 6 months before diagnosis, with persisting symptoms for the last 3 months.Exclusion criteria included indications of functional dyspepsia or other functional gastrointestinal disorders; active psychiatric conditions; and consumption of supplements or medications that would interfere with the gut’s natural microbiota, such as antibiotics, within the last 21 days before screening. In addition, subjects with gastrointestinal disorders or other digestive problems such as Crohn disease, short bowel, ulcerative colitis confirmed by fecal calprotectin negative test, constipation, and lactose intolerance were also excluded. Subjects who used gastrointestinal medications to control gut function, such as antispasmodics, prokinetic agents, probiotics, prebiotics, or laxatives, were excluded from the study. | PMC9982755 |
2.6. Randomization, blinding, and intervention | Subjects were randomized using computer-generated random allocation software (STATA Software version 16.0, StataCorp LLC, College Station, TX). An alphabetic code was generated for both the | PMC9982755 |
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2.7. Outcome measures | burping | ADVERSE EVENTS, SECONDARY, BRAIN | The participants completed all the 15 questions in the GSRS questionnaire. Three questions related to feeling bloated, bothered by burping and passing gas or flatus were considered as indigestion subscale. The primary outcome was the change in the cumulative indigestion score from screening to end of the study. Change in the global evaluation of patients’ scores, (a 10-point visual analogue scale where 1 is bad and 10 is good) from screening to the final visit was another primary outcome measure. The scores were assessed at the screening visit (visit 1), visit 3 (day 15), and the final visit (day 30).The secondary outcomes were a change in other subscale scores in the GSRS questionnaire, excluding the indigestion score from screening to the final visit; a change in Bristol stool analysis from screening to the final visit; a change in brain fog questionnaire score from screening to the final visit; and safety by assessing the adverse events. The Bristol stool chart and the Brain Fog questionnaire were assessed at the screening and final visits, while adverse events were monitored throughout the study. As a part of safety, laboratory parameters like hematology, renal function test, liver function test, and urine analysis were performed at screening and the final visit. | PMC9982755 |
2.8. Statistical analysis | All the statistical analysis was performed by STATA Software version 16.0. The GSRS Indigestion subscale score, global evaluation of patient scores, and other cumulative subscale scores in the GSRS questionnaire were represented as continuous variables.A comparative analysis was performed for normally distributed data within the group, and the results were presented as mean, standard deviation/standard error, and | PMC9982755 |
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3. Results | PMC9982755 |
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3.1. Demographic characteristics | abdominal bloating | A total of 87 subjects were screened, at the participating hospitals for the presence of functional abdominal bloating as per the inclusion/exclusion criteria, and 70 (29 males and 41 females) were enrolled and randomized to the Baseline demographics and vitals.Mean ± SD, (Min, Max) values are given for the baseline demographics.BMI = body mass index, GSRS = gastrointestinal symptom rating scale.CONSORT flow diagram. | PMC9982755 |
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3.1.1. Primary outcome parameters. | PMC9982755 |
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3.2. Secondary outcomes | PMC9982755 |
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3.2.1. GSRS scores (excluding indigestion subscale). | diarrhea, abdominal pain, constipation, diarrheal, subscale).Comparison, reflux syndrome | The GSRS cumulative scores for abdominal pain, reflux syndrome, diarrhea, and constipation subscales significantly improved in individuals consuming Cumulative GSRS questionnaire (excluding indigestion subscale).Comparison of cumulative GSRS Questionnaire, including abdominal pain, reflux syndrome, diarrheal, and constipation values between the treatment groups. Values are represented as Median and Range (Min, Max).GSRS = gastrointestinal symptom rating scale.
| PMC9982755 |
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3.2.2. Safety assessment. | PMC9982755 |
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3.2.2.1. Brain fog questionnaire | SIBO | In some studies, use of probiotics has been reported to be associated with brain fog in SIBO patients. The brain fog questionnaire was included and analyzed in the study as part of the safety outcome. One subject with brain fog in the | PMC9982755 |
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3.2.3. Safety parameters. | ADVERSE EVENTS, ADVERSE EVENT | One participant from the Summary of adverse events for all subjects.A total of 70 subjects were enrolled and 66 subjects completed the study. One subject in SAE = serious adverse event. | PMC9982755 |
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5. Conclusion | bloating, gastrointestinal disorders | GASTROINTESTINAL DISORDERS | Gas and bloating symptoms are common signs of gastrointestinal disorders affecting a larger population. | PMC9982755 |
Acknowledgments | We would like to thank the investigators, Dr Manjunath Patil and Dr Santosh Saklecha, and the entire clinical research team from the Sami-Sabinsa group, MS Ramaiah Medical College and Hospitals, and Santosh Hospital, Bangalore. The authors thank the statistician Mr. Kamal Kammili, M/s. Sanjeevani Bio Services Pvt. Ltd., who independently analyzed the data. | PMC9982755 |
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Supplementary Material | PMC9982755 |
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Abbreviations: | functional bowel disordersgastrointestinalgastrointestinal symptom rating scaleirritable bowel syndromesmall intestinal bacterial overgrowthSupplemental Digital Content is available for this article.Trial registration: CTRI/2019/06/019617.The authors have no funding to disclose.All the authors are employees of Sami-Sabinsa Group Limited or Sabinsa Corporation.The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.The authors, MM, KN, SP, SA, and LM, are affiliated with Sami -Sabinsa Group Limited or Sabinsa Corporation.How to cite this article: Majeed M, Nagabhushanam K, Paulose S, Arumugam S, Mundkur L. The effects of | PMC9982755 |
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