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Composite cognitive scores | Participants underwent a detailed neuropsychological examination [The executive function composite score was created from four established measures of executive function: the Digit Span backward (raw score), Trail Making Test part B (response time), Stroop interference index (response time for interference-naming items) and Letter Fluency (number of words beginning with P letter provided in 2 minutes). For each test, z-scores were computed using the total sample’s mean score and standard deviation. Trail Making Test and Stroop scores were reversed so that higher scores always indicate better performance. The executive function composite score corresponds to the unweighted average of these four z-scores.The episodic memory composite score was created from two established measures of episodic memory: The California Verbal Learning Test (CVLT) and the Wechsler Memory Scale IV Logical Memory, Story B (WMS IV) More specifically, the CVLT scores included the sum of trials 1–5, immediate free recall and delayed free recall, while the Logical Memory scores included immediate and delayed free recall. As for the executive composite, each sub-score was standardized using Age-Well baseline sample average score and standard deviation. The episodic memory composite score corresponds to the unweighted average of these five z-scores.Finally, to facilitate data interpretation, the cognitive composite scores were re-standardized (subtracting the average of the total sample and dividing by standard deviation of the total sample). In both cases, higher scores indicated better performance. | PMC10564409 | ||
Cognitive reserve proxies | cognitive, social and physical activities | Participants completed the French versions of the Cognitive Activities Questionnaire (CAQ) [The CAQ assesses cognitive activities for different life periods: at age 6, age 12, age 18, age 40, and for the current period [The LEQ assesses complex mental activities (e.g., education, occupational complexity, cognitive, social and physical activities) across 3 life periods: young adulthood (13–30 years), mid-life (30–65 years) and late life (from 65 years to present date) [For both questionnaires, higher scores reflect greater engagement in cognitive and/or complex mental activities, therefore greater CR. | PMC10564409 | |
Statistical analyses | SLEEP APNEA, INTERACTION, REGRESSIONS | First, we assessed the associations between age, sex and our measures of interest (% SWS, composite cognitive scores and CR proxies) using either correlations for continuous variables (age) or Third, using multiple linear regressions, we tested the interaction between each CR proxy (education, CAQ total, early life, mid-life, late life and LEQ total, young, mid-life and late life; entered separately in independent models) and SWS on each cognitive composite score, adjusting for age and sex, as follows: Cognition ~ SWS * CR proxy + Age + Sex. Interaction models were replicated to address potential confounds and assess the robustness of our findings while considering the influence of AHI, continuous positive airway pressure (CPAP) treatment at inclusion, adaptation night to the PSG device, sex differences or potential outliers. In order to consider sleep apnea, which may have an impact on both sleep architecture and cognition, we repeated our interaction analyses adjusting for AHI and by splitting the sample with a AHI clinical cutoff value of ≥ 15 [Analyses were performed using the R 4.0.2 software, and were considered significant at | PMC10564409 | |
Data availability | Data is available on request following a formal data sharing agreement and approval by the consortium and executive committee. The data sharing request form can be downloaded at | PMC10564409 | ||
Medit-Ageing Research Group | LUTZ | Florence Allais, Eider M Arenaza Urquijo, Julien Asselineau, Pierre Champetier, Anne Chocat, Sophie Dautricourt, Robin de Flores, Eglantine Ferrand Devouge, Eric Frison, Valérie Lefranc, Antoine Lutz, Géraldine Poisnel, Anne Quillard, Eric Salmon, Edelweiss Touron. | PMC10564409 | |
Supplementary Materials | PMC10564409 | |||
REFERENCES | PMC10564409 | |||
2. Materials and Methods | PMC10607930 | |||
2.1. Study Design and Study Participants | This prospective, single-centered, and randomized controlled trial was conducted in Derince Training and Research Hospital from September 2018 to September 2019. The study was conducted in accordance with the Declaration of Helsinki and approved by the Kocaeli University Ethical Committee of Clinical Research (KOU KIA 2018/260). The study was registered on clinicaltrials.gov (trial registration number: 02/08/2018 NCT03614845). Before randomization, written informed consent was obtained from all participants during preoperative evaluation. The study adhered to the reporting standards established by the Consolidated Standards of Reporting Trials (CONSORT). | PMC10607930 | ||
2.2. Selection and Exclusion Criteria | atelectasis, anesthesia-induced | ATELECTASIS | Eligible patients were American Society of Anesthesiologists (ASA) I-II patients aged between 18 and 75 years who were scheduled for laparoscopic cholecystectomy. There are patient-induced, surgical-induced, and anesthesia-induced risk factors in the development of perioperative atelectasis [ | PMC10607930 |
2.3. Randomization and Blinding | LUNG, BLIND | The patients were divided into two groups with the closed envelope method to undergo either volume-controlled ventilation (Group V) or pressure-controlled volume-guaranteed ventilation (Group PV). Opaque envelopes with sequential numbers were created by an individual who was not involved in the study. These envelopes were opened by an independent party who was also not involved in the study or the preparation of the envelopes. Intraoperative hemodynamic data and ventilation parameters, predetermined in the study protocol, were recorded on patient monitors and subsequently transcribed onto paper case report forms by an anesthesia assistant who was blinded to the protocol and hypothesis of the study and group assignments. Lung ultrasonography was performed by an anesthesiologist who was blind to the study groups and experienced in lung ultrasonography. | PMC10607930 | |
2.4. Anesthesia and Surgical Procedure | bleeding, hemorrhages, ’ | BLEEDING, HEMORRHAGES | In the operating room, the patients were monitored in terms of an electrocardiogram (EKG), peripheral oxygen saturation, noninvasive blood pressure, heart rate, and body temperature. Following the induction of anesthesia, the end-tidal COFor anesthesia induction, patients were given an IV bolus dose of propofol 2 mg/kg, fentanyl 2–3 μg/kg, and rocuronium bromide 0.6 mg/kg. Then, they were intubated with a cuffed endotracheal tube. While 7–7.5 mm tubes were used for women, 8–8.5 mm tubes were used for men. IV remifentanil infusion (0.2 μg/kg/min) and Sevoflurane 2% in a 1:1 air:oxygen mixture were used to maintain anesthesia. Low-flow anesthesia was used with a fresh gas flow rate of 1 L/min; an inspired oxygen concentration (FIO2) of 0.5 was provided along with air. The oxygen saturation was targeted above 93% throughout the operation [In the perioperative period, the peak and plateau inspiratory pressures (IP), dynamic compliance, respiratory rate, exhaled tidal volume and ETCOThe patients’ perioperative fluid requirement was met through 5 mL/kg/hr IV infusion of crystalloid solutions. In case of perioperative bleeding, the first 500 mL was compensated with colloid liquids. Continuous hemorrhages were replaced with blood after estimating the blood volume patients lost. At the end of surgery, CO | PMC10607930 |
2.5. Lung Ultrasonography | fits | LUNG | Lung ultrasonography was performed with a Mindray M5 Mobile TrolleyThe thorax was divided into 12 quadrants according to the anterior and posterior axillary line in both the right and left lung areas; anterior, lateral, and posterior zones were identified, and the upper and lower regions (R1, R2 … R6; L1, L2 … L3) of these zones were also visualized. (During laparoscopic cholecystectomy procedures, patients are placed in the Trendelenburg position in order to enhance surgical vision. However, as the surgical area is located in the upper right quadrant, the most critical anatomical area for surgical manipulation is the area under the right diaphragm, which fits under the right lung. For these reasons, we sought to conduct a detailed analysis of the LUS score in each region. | PMC10607930 |
2.6. Outcome Measurement of the Study | SECONDARY | Outcomes measures: the primary outcome of the present study is the difference in the LUS score between the two groups in postoperative periods T2 and T3; secondary outcomes include the plateau pressure, peak inspiratory pressure, and compliance differences between the groups at (T | PMC10607930 | |
2.7. Statistical Analysis | The SPSS 22.0 program was used for analysis. We used the mean, standard deviation, median, minimum, maximum, frequency, and ratio values for descriptive statistics. The distribution of variables was measured with the Kolmogorov–Smirnov test. As we had a small sample size, it was important to determine the distribution of the variable in order to choose an appropriate statistical method, so the Shapiro–Wilk test was performed and showed non-normality, and the results were consistent with the Kolmogorov–Smirnov test. The Kruskal–Wallis and the Mann–Whitney tests were used in the analysis of quantitative independent data. Dependent quantitative data were analyzed with the Wilcoxon test. Quantitative independent data were analyzed using the chi-square test, but when the conditions for the chi-square test were not met, we used the Fisher test. For the analysis of repeated data, the repeated measures ANOVA was used. The calculation of the sample size was based on a previous study [ | PMC10607930 | ||
3. Results | PMC10607930 | |||
3.1. Analyses of Demographics and Surgical Data | PMC10607930 | |||
3.1.1. Demographic and Surgical Characteristics | In total, 102 patients were followed up for this study. Twenty-four patients declined to participate in the study, and five patients did not meet the criteria for inclusion. Nine patients were excluded from the study due to missing data, and two patients had their surgeries switched from laparoscopy to laparotomy. In conclusion, 62 patients’ data were analyzed.The patients were aged from 19 to 75 years of age (48.66 ± 15.15 years). While 31 patients received the PCV-VG mode, the other 31 patients received the VCV mode. Of the study participants, 46 (74.2%) were female and 16 (25.8%) were male.The demographic and surgical data were statistically similar between the two groups of the patients participating in the study ( | PMC10607930 | ||
3.1.2. Analyses of Hemodynamic Parameters | The mean arterial pressure (MAP) and heart rate during the perioperative period were found to be similar. The ventilator parameters of the SPO | PMC10607930 | ||
3.2. Analyses of LUS Scores | The total LUS scores were statistically significantly similar between the groups (However, when the change in LUS measurements was investigated by region, the postoperative L2, L4, L5, L6, R2, R3, R4, R5, and R6 values of the patients in the PV group were statistically significantly higher compared to the preoperative values (In the V group, on the other hand, the postoperative L1, L2, L3, L5, L6, R1, R2, R3, R4, R5, and R6 values were statistically significantly higher than the preoperative L1, L2, L3, L5, L6, R1, R2, R3, R4, R5, and R6 values (The change in the postoperative LUS score in the R2 region was statistically significantly higher in the V group compared to the PV group (There was no significant difference between the two groups in the mean intraabdominal pressure, and the maximum intra-abdominal pressure was kept around 15 mmHg. | PMC10607930 | ||
3.3. Analyses of Ventilator Parameters | PNEUMOPERITONEUM | The peak inspiratory pressure value prior to the pneumoperitoneum was statistically significantly higher in the V group as compared to the PV group (The plateau pressure measurements were statistically significantly higher in the V group as compared to the PV group (The compliance measurements were statistically significantly lower in the V group as compared to the PV group (The compliance value after pneumoperitoneum was statistically significantly lower compared to the other time measures ( | PMC10607930 | |
4. Discussion | pleural effusion, atelectasis, PCV-VG, respiratory and cardiac illnesses, aeration loss with postoperative LUS, aeration loss, barotrauma | PLEURAL EFFUSION, ATELECTASIS, COMPLICATION | Using lung ultrasound, we found that aeration loss occurs during laparoscopic cholecystectomy in this randomized controlled trial. The ventilation modes, VCV and PCV-VG, did not influence the development and amount of atelectasis. LUS scores showed less aeration loss in the PCV-VG group only in the right region. The PCV-VG ventilation mode was associated with better lung mechanics in the patients.In our study, the results of the analysis of the mechanical ventilation parameters may be attributed to some advantages that the PCV-VG mode provides over the VCV. The PCV-VG mode delivers the preset tidal volume with a decelerating flow at the lowest possible pressure. When using the pressure-controlled ventilation mode, the required tidal volume is provided to the patient performing the compliance changes required to achieve a consistent tidal volume. The PCV-VG offers the benefits of PCV with better oxygenation and the security of consistent tidal volume. Due to all these reasons, the PCV-VG is useful for any surgical procedure including laparoscopy, where the patient’s compliance is expected to change perioperatively. As compared to volume-controlled ventilation, it provides better oxygenation at lower peak inspiratory pressures and higher mean airway pressures [Volume-controlled ventilation has been the traditional mode of controlled ventilation in anesthesia. In VCV, the ventilator delivers the preset tidal volume with a constant flow at the preset respiratory rate during a preset inspiratory time. It has been the preferred mode of mechanical ventilation in anesthesia applications due to its ability to control Minute Volume. However, the VCV uses a constant flow that may cause high peak pressures and thus expose the patient to the risk of barotrauma [Similarly in the study of Assad et al., the PCV-VG mode was determined to be superior to the VCV mode with a significantly lower peak inspiratory pressure and greater dynamic compliance than the VCV mode [Another study on laparoscopic gynecological surgeries drew a comparison between VCV and PCV and reported a significant increase in the peak airway pressure, compliance, plateau pressure, and airway resistance when VCV was used [One of the unique features of our study is that we evaluated aeration loss with postoperative LUS scores. When the LUS scores were evaluated, it was observed that all patients developed aeration loss following laparoscopic surgery with elevated LUS scores. The increase in the incidence of aeration loss in these patients was regardless of the perioperative mechanical ventilation parameters. However, it is worthy of note that the change in the postoperative LUS score inferoanterior zone of the right lung was significantly greater in the V group compared to the PV group. Another advantage besides effective ventilation was that atelectasis complication did not occur.In addition to intraoperative techniques to prevent atelectasis in abdominal surgeries, it would be pertinent to discuss several postoperative strategies. These include the use of noninvasive ventilator support or high-flow nasal cannula in high-risk patients such as those with a BMI > 30, respiratory and cardiac illnesses, prolonged surgery duration, and major surgery. Both these strategies can be employed as prophylactics, as well as therapeutics, in the postoperative period.Strategies to prevent atelectasis in the postoperative period include early mobilization, respiratory physiotherapy that expands the lungs, non-opioid analgesia that is effective, oxygen therapy, mucolytics, eliminating causes that may cause external compression of the thorax, reducing abdominal pressure, evacuating the stomach with a nasogastric tube, and draining any pleural effusion that may be present in the thorax [ | PMC10607930 |
Limitations | obese, atelectasis | OBESE, ATELECTASIS | The major limitation of the present study is that while the sample size and expressive power of our study are sufficient, it is important to note that this study was conducted on a singular type of surgery and a specific patient group. Further studies will need to include larger series and more diverse patient groups; for example, obese patients, patients with severe cardiopulmonary problems, the pediatric age group, and patients undergoing different types of surgery. Another limitation is that ultrasonography was used for the diagnosis of atelectasis only in the postoperative period, whereas frequent intraoperative measurements of LUS score may detect atelectasis accurately. | PMC10607930 |
Supplementary Materials | The following supporting information can be downloaded at Click here for additional data file. | PMC10607930 | ||
Author Contributions | Conceptualization, K.T.S., A.S. and A.Z.T.C.; methodology, K.T.S. and A.S.; formal analysis, K.T.S. and A.Z.T.C.; investigation, A.S. and K.T.S.; data curation, A.Z.T.C.; writing—original draft preparation, K.T.S. and A.Z.T.C. writing—review and editing, A.S., K.T.S. and A.Z.T.C.; All authors have read and agreed to the published version of the manuscript. | PMC10607930 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Kocaeli University Ethical Committee of Clinical Research (KOU KIA2018/260; approved on 5 June 2018). | PMC10607930 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10607930 | ||
Data Availability Statement | The authors confirmed that the data supporting the findings of this study are available within the article and its | PMC10607930 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10607930 | ||
Graphical Abstract | tremor-related impairment, tremor | REGRESSION | Members of Transplantlines Investigators are listed at the end of articleSolid organ transplant recipients (SOTR) frequently report tremor. Data concerning tremor-related impairment and its potential impact on health-related quality of life (HRQoL) are lacking. This cross-sectional study assesses impact of tremor on activities of daily living and HRQoL using validated questionnaires among SOTR enrolled in the TransplantLines Biobank and Cohort Study. We included 689 SOTR (38.5% female, mean [±SD] age 58 [±14] years) at median [interquartile range] 3 [1–9] years after transplantation, of which 287 (41.7%) reported mild or severe tremor. In multinomial logistic regression analyses, whole blood tacrolimus trough concentration was an independent determinant of mild tremor (OR per µg/L increase: 1.11, 95% CI: 1.02 to 1.21,
| PMC10062599 |
Introduction | tremor-related impairment, tremor, tremor-related ADL impairment, end-stage organ failure | DISEASES | Solid organ transplantation has evolved from a scientific novelty to the preferred treatment for end-stage organ failure. For example, kidney, liver, lung, and heart transplantations strongly improve long-term survival in otherwise untreatable diseases (One of the most frequently reported side effects of CNIs is the development of tremor: rhythmic, sinusoidal oscillations of the limbs, head, or trunk (CNI-induced tremor generally occurs soon after initiation of CNI maintenance therapy (We therefore aimed to assess the prevalence and severity of tremor-related ADL impairment among SOTR. Additionally, we aimed to identify clinical, biochemical, and pharmaceutical factors that may predispose SOTR for the development of tremor-related impairment. Finally, we assessed associations of tremor-related impairment with HRQoL. | PMC10062599 |
Materials and Methods | PMC10062599 | |||
Design and Study Population | tremor | For this cross-sectional study, data from the TransplantLines Biobank and Cohort Study (For the current study, all enrolled SOTR with a functioning allograft for at least 6 months, with available data on tremor influence on ADL between September 2016 and November 2020, were included. A consort flow diagram is shown in | PMC10062599 | |
Immunosuppressive Regimen | All included SOTR attended the outpatient clinic of the UMCG and were treated according to standard immunosuppressive therapies, with revision of therapy effectiveness at least once per year. Immunosuppressive maintenance therapies were generally tacrolimus-based, with addition of mycophenolate mofetil (MMF), and prednisolone. Other immunosuppressive drugs used less frequently were cyclosporine, everolimus, sirolimus, and azathioprine. Although immunosuppressive regimens may be adapted on an individual basis, standard protocol target trough concentrations of tacrolimus and cyclosporine in the UMCG are shown in Immunosuppressive target trough concentration per transplant type in the UMCG.
∼ target trough concentrations are not listed in UMCG protocols. *Cyclosporine is not used for this type of transplantation. | PMC10062599 | ||
Laboratory Methods | BLOOD | Blood was drawn in the morning after an overnight fasting period of at least 8 h, including no medication use. All tacrolimus and cyclosporine whole blood trough concentrations were determined by validated liquid chromatography mass-spectrometry analyses at the UMCG ( | PMC10062599 | |
Tremor Rating | tremor, Tremor | Tremor severity was assessed using a Dutch translation of the Fahn-Tolosa-Marin (FTM) tremor rating scale part C (TRS-C) ( | PMC10062599 | |
Health-Related Quality of Life | pain | HRQoL was assessed using the 36-Item Short Form health survey, which is a validated questionnaire to assess several health domains, including physical functioning, role limitations due to physical health, role limitations due to emotional problems, vitality, emotional wellbeing, social functioning, pain, and general health perceptions ( | PMC10062599 | |
Additional Data Collection | BLOOD | Blood pressure and heart rate were measured with a semi-automatic device (Philips Suresign VS2+, Andover, Massachusetts, USA). Body weight and height were measured with participants wearing indoor clothing without shoes. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m | PMC10062599 | |
Statistical Analyses | tremor | REGRESSION | Dispersion of TRS-C scores in total, and per transplant type, were visualized by means of pie charts and bar charts. Patient characteristics are presented and compared in patients without tremor, with mild tremor, and with severe tremor. Continuous variables are summarized as mean ± SD or median [interquartile range], depending on distribution, whereas categorical or dichotomous variables are presented as count (%). To assess differences between tremor severity groups, Analyses of Variance were used for normally distributed variables, Kruskal-Wallis tests for non-normally distributed variables and Chi-squared tests for categorical variables. To assess associations of tremor severity with clinical, biochemical and pharmacotherapeutic parameters, multinomial logistic regression analyses, adjusted for sex, age, and logDifferences in PCS and MCS between grades of tremor severity were visualised with boxplots. Analyses of variance were performed for testing significance of differences between the different grades. Furthermore, bivariable linear regression analyses with PCS and MCS as dependent variable were performed to assess associations of mild and severe tremor with HRQoL. In multivariable linear regression analyses we assessed the association of mild and severe tremor with HRQoL, while adjusting for potential confounders including age, sex, type of transplantation, logScatterplots and QQ-plots were visually evaluated to assess data distribution. Non-normally distributed variables were transformed using a binary logarithm (log | PMC10062599 |
Results | PMC10062599 | |||
Baseline Characteristics | tremor | In total, 689 SOTR were included in the current study, including kidney (Characteristics of 689 SOTR without tremor, with mild tremor, or with severe tremor, based on the TRS-C total score.*Percentages were calculated by dividing the number of patients in each transplant type by the total number of all solid organ transplant patients with no/mild/severe tremor. Bold type indicates significance of results.eGFR, estimated glomerular filtration rate as calculated using CKD-EPI formula. Normally distributed data are presented as mean ± standard deviation, skewed data as median [interquartile range], and categorical data as number (valid percentage). | PMC10062599 | |
Occurrence of Tremor and Impact on Activities of Daily Life | tremor | 206 (29.9%) SOTR reported mild tremor and 81 (11.8%) reported severe tremor. Mild or severe tremor was reported in 39.7% among kidney transplant recipients, 33.9% among liver transplant recipients, 57.9% among lung transplant recipients, and 55.1% among heart transplant recipients. TRS-C scores of all SOTR and per organ type are shown in
Bar charts of tremor severity group distribution per transplant type. | PMC10062599 | |
Determinants of Tremor-Related Impairment | tremor | REGRESSION | Results of multinomial logistic regression analyses adjusted for age, sex, and logMultinomial logistic regression analyses of tremor severity with adjustment for age, sex, and logBold type indicates significance of results. log | PMC10062599 |
Health-Related Quality of Life | tremor | REGRESSION | SOTR that reported mild or severe tremor had significantly lower physical and mental HRQoL, as visualized in Boxplots of PCS, and MCS for HRQoL in 689 SOTR (mild and severe tremor present in 206 (29.9%) and 81 (11.8%) SOTR, respectively). The PCS, and MCS differed significantly between groups as calculated using Analyses of Variance (Linear regression analyses of tremor severity with physical and mental HRQoL.95% CI, 95% confidence interval; PCS, physical component summary; MCS, mental component summary; eGFR, estimated glomerular filtration rate; HRQoL, health-related quality of life. | PMC10062599 |
Discussion | tremor, tremor-related impairments, medication-induced tremor, tremor-related impairment, diabetes | PATHOPHYSIOLOGY, DIABETES | This study shows that mild or severe tremor frequently impairs daily life activities of SOTR. Tacrolimus trough concentration was a main determinant of tremor. Importantly, mild and severe tremor-related impairments were strongly associated with lower HRQoL, independent of other known determinants of tremor.Our results confirm that SOTR frequently experience tremor-related impairment of ADL. A previous study reported similar tremor prevalence compared to our study (The notion that tacrolimus trough concentrations are independently associated with tremor-related impairment among SOTR is important for treating physicians to consider during treatment regimens. Furthermore, this notion highlights the need for alternative immunosuppressive treatment regimens that are less likely to cause tremor, while maintaining low risks of rejection. Since dose-dependency seems to be key in the pathophysiology of medication-induced tremor, extended-release preparations may be able to reduce tremor prevalence by reducing peak-to-trough variability (The potential impact of tremor on the lives of SOTR is further highlighted by the associations of severe tremor with both lower mental and physical HRQoL. These results are generally in line with findings in previous smaller studies. For example, Langone et al. reported an improved quality of life after a reduction in tremor severity, in a small cohort of 38 kidney transplant recipients (A major strength of this study is the large number of included SOTR with available data regarding subjective tremor and HRQoL. Additionally, we included kidney, liver, lung, heart, and small intestine transplant recipients, allowing for evaluation of tremor prevalence among these patient groups. In addition, the cohort was well-characterized, allowing us to adjust for many potential confounders, including extensive clinical data, laboratory measurements, and treatment regimens. A limitation of the current study is that the participants mainly used tacrolimus-based treatment regimens, and associations of cyclosporine and other immunosuppressive drugs with tremor could therefore be incompletely studied. In addition, since patients were not evaluated before transplantation, the presence and exacerbation of preconditions which may cause tremor could not be assessed. Non-CNI users with tremor more frequently had diabetes compared to those without diabetes, which may partly explain the high prevalence of tremor in this subgroup. Nevertheless, this observation cannot fully explain the tremor occurrence in this subgroup, and future studies are needed to gain insights into the tremor susceptibility of some SOTR without CNI-use. Lastly, due to the observational design of the study, we cannot draw conclusions regarding causality of our findings. Moreover, the current cross-sectional study cannot identify trajectories of tremor before and after transplantation, and therefore longitudinal studies assessing the determinants of tremor are warranted. Such studies may also help to account for potential tacrolimus dosage adaptations that clinicians may conduct in patients with severe tremor.SOTR frequently report tremor-related impairment of ADL. Tacrolimus trough concentrations appeared a main determinant of tremor among SOTR. The strong and independent association of tremor-related impairment with lower HRQoL warrants further studies into the effects of tacrolimus on tremor. | PMC10062599 |
Members of Transplantlines Investigators | P., A. Pol | MARION, FRANK | Coby Annema, Stephan J. L. Bakker, Stefan P. Berger, Hans Blokzijl, Frank A. J. A. Bodewes, Marieke T. de Boer, Kevin Damman, Martin H. de Borst, Arjan Diepstra, Gerard Dijkstra, Caecilia S. E. Doorenbos, Rianne M. Douwes, Michele F. Eisenga, Michele E. Erasmus, C. Tji Gan, Antonio W. Gomes Neto, Eelko Hak, Bouke G. Hepkema, Frank Klont, Tim J. Knobbe, Daan Kremer, Henri G. D. Leuvenink, Willem S. Lexmond, Vincent E. de Meijer, Hubert G. M. Niesters, Gertrude J. Nieuwenhuijs - Moeke, L. Joost van Pelt, Robert A. Pol, Adelita V. Ranchor, Jan Stephan F. Sanders, Marion J. Siebelink, Riemer J. H. J. A. Slart, J. Casper Swarte, Daan J. Touw, Marius C. van den Heuvel, Coretta van Leer-Buter, Marco van Londen, Erik A. M. Verschuuren, Michel J. Vos, Rinse K. Weersma. | PMC10062599 |
Data Availability Statement | The datasets presented in this article are not readily available because public participant data sharing is not included in the TransplantLines informed consent forms. Data requests are only legally allowed after approval by the TransplantLines Scientific Committee upon reasonable request, in accordance with the medical ethical committee allowance and the UMCG Biobank Regulations. Requests to access the datasets should be directed to the corresponding author. | PMC10062599 | ||
Ethics Statement | The studies involving human participants were reviewed and approved by METc University Medical Centre Groningen 2014/077. The patients/participants provided their written informed consent to participate in this study. | PMC10062599 | ||
Author contributions | NR and DK wrote the draft manuscript. NR and DK performed data analyses. DK, AG-N, and ME performed the research and contributed to data collection. TK contributed to data collection, interpretation, and manuscript revisions. CG, SN, HB, VM, KD, GD, JE, SB, and DT were responsible for the research design and manuscript revisions. SB and AS were responsible for the research design, contributed to data interpretation and manuscript revisions. All authors read and approved the final manuscript. | PMC10062599 | ||
Conflict of Interest | The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10062599 | ||
Supplementary Material | The Supplementary Material for this article can be found online at: Click here for additional data file. | PMC10062599 | ||
Abbreviations | tremor | ADL, Activities of daily living; CNI, Calcineurin inhibitor; FTM TRS-C, Fahn-Tolosa-Marin tremor rating scale C; HRQoL, Health-related quality of life; MCS, Mental component summary; PCS, Physical component summary; SOTR, Solid organ transplant recipients. | PMC10062599 | |
References | PMC10062599 | |||
Abstract | PMC10807909 | |||
Context | T2D | TYPE 2 DIABETES | Treatments that reduce postprandial glycemia (PPG) independent of stimulating insulin secretion are appealing for the management of type 2 diabetes (T2D). Consuming pre-meal whey protein (WP) reduces PPG by delaying gastric emptying and increasing plasma insulin concentrations. However, its effects on β-cell function and insulin kinetics remains unclear. | PMC10807909 |
Objective | To examine the PPG-regulatory effects of pre-meal WP by modeling insulin secretion rates (ISR), insulin clearance, and β-cell function. | PMC10807909 | ||
Methods | T2D | This was a single-blind, randomized, placebo-controlled, crossover design study in 18 adults with T2D (HbA | PMC10807909 | |
Results | β-cell function was 40% greater after WP ( | PMC10807909 | ||
Conclusion | T2D | TYPE 2 DIABETES | In adults with T2D, pre-meal WP reduced PPG by coordinating an enhancement in β-cell function with a reduction in insulin clearance. This enabled an efficient postprandial insulinemic profile to be achieved without requiring further β-cell stimulation.Trial registry ISRCTN ID: ISRCTN17563146
For most people with controlled type 2 diabetes (T2D), controlling postprandial glycemic (PPG) excursions are fundamental to achieving optimal glycemic control (Nutritional therapies are central to the care of T2D (It is well appreciated that major determinants of PPG include the rate of gastric emptying and the secretion of insulin (While much research has focused on the gastrointestinal responses following pre-meal WP supplementation, its effects on insulin kinetics and β-cell function remain unknown. We, therefore, examined the mechanisms by which pre-meal WP reduces PPG in people with T2D using a validated model of insulin kinetics and β-cell function. It was hypothesized that a pre-meal WP bolus would amplify the secretion of insulin, while modestly reducing the metabolic clearance rate of insulin (MCRi) ( | PMC10807909 |
Methods | PMC10807909 | |||
Ethical Approval | The presented data were collected as part of a wider study ( | PMC10807909 | ||
Participant Recruitment and Eligibility | T2D | Individuals with T2D from the North East of England were recruited by study advertisements. Inclusion criteria were age 30 to 60 years, duration of T2D of ≥ 1 year, stable treatment with lifestyle and/or oral medications for ≥ 3 months, glycated hemoglobin (HbAParticipant recruitment and testing were conducted between March 2019 and September 2021. A total of 26 participants were recruited for this study. From this cohort, 8 participants were withdrawn for the following reasons: 1 participant withdrew their consent prior to randomization; 3 participants were withdrawn due abnormal laboratory findings (laboratory measured HbAParticipant flow through a randomized, placebo-controlled crossover trial.Patient clinical characteristicsWhere appropriate, data are presented as means ± SD (range).Abbreviations: SGLT2i, sodium-glucose cotransporter 2 inhibitor; SU, sulfonylureas; TZD, thiazolidinediones. | PMC10807909 | |
Study Design | This was a single-blind, randomized, placebo-controlled, crossover study assessing the influence of pre-meal WP on parameters of glycemic control ( | PMC10807909 | ||
Procedures | Thirty-six hours before each mixed-meal test, participants were fitted with a continuous glucose monitoring system (Dexcom G6, Dexcom, Inc., USA) that was implanted into the subcutaneous tissue of the anterior-medial aspect of the abdomen (Participants arrived at the Newcastle NIHR Clinical Research Facility after an overnight fast (∼12 hours), having consumed a standardized meal (920 kcal derived 47%, 17%, and 36% from carbohydrates, protein, and fat, respectively) the previous evening (∼1900-2000 hours). Once rested, an intravenous cannula was introduced into a forearm vein for repeated blood sampling. Participants then consumed a WP (100 kcal, 15.6 g protein) or placebo (35 kcal, < .1 g protein) shot 10 minutes before a breakfast meal consisting of 60 g of ready-to-eat cereal (Cheerios, Nestle, UK) and 250 mL of whole milk (387 kcal from 58% carbohydrates, 27% fat, and 15% protein). The breakfast meal was initiated at | PMC10807909 | ||
Pre-Meal Treatments | Patients were provided with 2 pre-meal shots created specifically for free-living glucose management (Arla Foods Ingredients Group P/S, Viby J, Denmark). Both the WP and placebo shots were presented as a 100 mL beverage in a ready-to-drink and contemporary format. Further details regarding to the pre-meal treatments and their acceptability in the free-living community are described elsewhere ( | PMC10807909 | ||
Sample Handling | For the analysis of C-peptide and insulin, blood samples were collected in serum collection tubes. For the analysis of glucagon, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, blood samples were collected in EDTA tubes containing aprotinin and a dipeptidyl-peptidase IV inhibitor. All collection tubes were centrifuged at 3000 rpm at 4 °C for 10 minutes and stored at −80 °C until analysis. PPG were measured by a Dexcom G6 continuous glucose monitoring system (Dexcom, Inc., USA). | PMC10807909 | ||
Calculations | The time-averaged incremental area under the curve (iAUC) (ie, the postprandial area above baseline concentrations [A single-pool model was used to describe insulin kinetics, as previously reported (Where VWhere Ins[t = −15] and Ins[t = 240] are plasma insulin concentrations at baseline ( | PMC10807909 | ||
Analytical Procedures | Serum insulin concentrations were determined using a commercially available enzyme-linked immunosorbent assay (ELISA) with an assay sensitivity of 6 pmol/L (intra-assay, < 8.9%; Cat# 10-1113-01, RRID:AB_2877672; Mercodia AB, Sweden). Serum C-peptide concentrations were measured using an ELISA with an assay sensitivity of < 25 pmol/L (intra-assay, < 10%; Cat# 10-1136-01, RRID:AB_2750847; Mercodia AB, Sweden). Plasma glucagon concentrations were measured using a sandwich ELISA employing monoclonal antibodies against the C- and N- terminal regions of glucagon with a detection limit of 0.75 pmol/L (intra-assay, < 4.3%; inter-assay, 9.0%; Cat 10-1271-01, RRID:AB_2737304; Mercodia AB, Sweden). Plasma GIP concentrations (ie, [1-42] and [3-42]) were analyzed by ELISA with an assay sensitivity of 1 pmol/L (intra-assay, < 5.4%; inter-assay, 10%; Cat# EZHGIP-54K, RRID:AB_2801401; Merck Millipore, USA). Plasma GLP-1 (ie, [7-36] NH | PMC10807909 | ||
Statistical Analysis | All data were assessed for normal distribution by a Shapiro-Wilks test. The data that were revealed to be not normally distributed were log | PMC10807909 | ||
Results | INSULIN SENSITIVITY | Fasting biochemical variables were similar between trials (Postprandial metabolic and modeling variables following consumption of a pre-meal WP or placebo shotData are presented as means ± SD or as median (IQR) for excessively skewed data. Analysis was conducted on all participants (n = 18) by a paired sampled Abbreviations: GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; iAUC, incremental area under the curve; ISR, insulin secretion rate; MCRi, metabolic clearance rate of insulin; OGIS, oral glucose insulin sensitivity index; PPG, postprandial glycemia; Rdins(t), rate of insulin extraction.and | PMC10807909 | |
Glucose | interstitial glucose, Preloads | Interstitial PPG concentrations increased following the ingestion of the mixed-nutrient breakfast, peaking at ∼Postprandial profiles (means with 95% CI) of interstitial glucose (A) insulin (B), C-peptide (C), glucagon (D), GIP (E), and GLP-1 (F) following ingestion of a WP (open) or a placebo (filled) preload shot. Preloads were consumed 10 minutes prior to a mixed-nutrient meal. Data were analyzed by a two-way repeated measures ANOVA (panels a, c, d, e, and f) or a Friedman's ranks test (panel b). Post hoc pairwise comparisons were performed with Bonferroni corrections. Results from the ANOVA are presented by treatment (Tx), time, and differences due to the interaction of | PMC10807909 | |
Insulin and C-peptide | The ingestion of the meal caused plasma insulin and C-peptide to increase from baseline values ( | PMC10807909 | ||
Glucagon | Plasma glucagon concentrations demonstrated significant main effects for both | PMC10807909 | ||
Incretin Peptides | During both experimental days, GIP increased from basal values following consumption of the test meal and remained elevated throughout the postprandial period (During both trials, GLP-1 concentrations increased from basal values following ingestion of the breakfast meal before returning to preprandial concentrations upon termination of the trial ( | PMC10807909 | ||
Insulin Kinetics | During both trials, ISR increased following the ingestion of the meal. Although WP potentiated an early increase in ISR, compared with placebo (Postprandial profiles (means with 95% CI) of ISR (A) MCRi (B) and RdFasting MCRi values were similar at the commencement of both trials but differed following the meal ( | PMC10807909 | ||
β-Cell Function and Whole-Body Insulin Sensitivity, | ΔISR/PPG÷IR was increased during the WP trial, relative to placebo (ratio of geometric means, 1.4 [95% CI, 1.16 to 1.69; | PMC10807909 | ||
Associations Between Insulin Secretion, Insulin Clearance, and Glycemia | Using pooled data, an inverse association between MCRi and glucagon iAUC | PMC10807909 | ||
Discussion | glucotoxicity, T2D | SECONDARY, DEPOLARIZATION, PATHOGENESIS | The present study investigated the effects of an acute dose of pre-meal WP (15 g) on pancreatic β-cell function and postprandial insulin kinetics, and their subsequent influence on PPG excursions in people with T2D. Our primary finding is that, at the whole-body level, pre-meal WP integrates a reciprocal mechanism that involves an enhancement in β-cell function with a reduction in insulin clearance (MCRi). This produces an effective plasma insulin profile to rising glucose concentrations without requiring further β-cell stimulation and insulin release.We confirm prior reports demonstrating that a low dose of pre-meal WP reduces PPG excursions in people with T2D (Despite enhancing β-cell function, overall insulin secretion was unaffected by our WP preload. Instead, our data indicate that pre-meal WP affects insulin kinetics, namely by reducing MCRi. This observation was intriguing, particularly since the decline in postprandial insulin clearance appears blunted in T2D (Our findings concerning the role of MCRi and ISR on PPG homeostasis following a WP preload are novel and may be of interest in the pathogenesis of T2D. As was demonstrated here, for individuals with compromised β-cell function, a reduction in postprandial MCRi enabled an appropriate insulin profile to be achieved without placing further stress on the β-cells for insulin release. This subsequently resulted in a 16% reduction in PPG iAUC, which may concomitantly improve β-cell viability through a reduction in glucotoxicity within the β-cell (While the mechanism(s) explaining the observed reduction in MCRi are unclear, explorative analysis highlighted an inverse relationship between glucagon iAUCAs anticipated, pre-meal WP augmented the early and sustained increase in GLP-1 secretion, which most likely reflects the rapid delivery of amino acids to the small intestine and the subsequent depolarization of the enteroendocrine L-cell (Strengths associated with our study include the randomized, placebo-controlled design and counterbalanced administration of treatments. Moreover, prehepatic ISR were calculated, thus circumventing interindividual hepatic and posthepatic insulin extraction. We also used a conventional mixed-nutrient meal to convey the expected islet and gastrointestinal responses to the ingestion of a commonly consumed meal, thereby increasing the real-world validity of our findings. Similarly, we chose to present our pre-meal shots at a time that was deemed more likely to embody free-living eating patterns. Nevertheless, it must be recognized that the reported data were secondary outcomes from our primary study (In summary, the ingestion of a low dose of pre-meal WP reduces PPG excursions in adults with T2D by coordinating an enhancement in β-cell function with a reduction in MCRi to produce an efficient plasma insulin profile. The reduction in insulin clearance may represent a counterregulatory response to an increase in glucagon signaling and hepatic glucose output. Studies tracing PPG fluxes with appropriate methodology following pre-meal WP warrant future evaluation. | PMC10807909 |
Acknowledgments | The authors thank the study participants for their time, effort, and commitment, as well as the research teams at the Newcastle National Institute for Health Research Clinical Research Facility, Newcastle upon Tyne, for their assistance with data collection. The authors thank Professor Roman Hovorka from the University of Cambridge (UK) for kindly providing access to the ISEC software programme. | PMC10807909 | ||
Funding | This work was supported by a grant awarded to D.J.W. and E.J.S (grant number: BH172513) from Arla Foods Ingredients Group P/S (Viby J, Denmark). Arla Foods Ingredients Group P/S produced the whey protein and placebo treatments. Arla Foods Ingredients Group P/S had no role in the collection, analysis, or interpretation of data. Continuous glucose monitoring systems were provided by an equipment award from Dexcom, Inc., (San Diego, USA) awarded to D.J.W. | PMC10807909 | ||
Author Contributions | K.S., E.J.S., and D.J.W. designed the research. K.S. conducted the research, analyzed the data, and wrote the manuscript. D.J.W. analyzed the data and wrote the manuscript. G.S.T., M.W., K.A.B., L.H.B., and E.J.S. reviewed and edited the manuscript. D.J.W. is the guarantor of this work and takes responsibility for the integrity of the data and the accuracy of data analysis. | PMC10807909 | ||
Disclosures | D.J.W. and E.J.S. have received research funding, travel expenses, and consultancy fees from Arla Foods Ingredients Group P/S. E.J.S. has received research funding from The Dairy Council. L.H.B. is an employee of Arla Foods Ingredients Group P/S. No other potential conflicts of interest related to this article were reported. | PMC10807909 | ||
Data Availability | The raw data supporting the conclusions of this article will be made available upon reasonable request. | PMC10807909 | ||
References | PMC10807909 | |||
Abbreviations | INSULIN SENSITIVITY | enzyme-linked immunosorbent assayglucose-dependent insulinotropic polypeptideglucagon-like peptide 1glycated hemoglobinincremental area under the curveinsulin secretion ratemetabolic clearance rate of insulinoral glucose insulin sensitivity indexpostprandial glycemiarate of insulin extractiontype 2 diabetesvolume distribution for insulinwhey protein | PMC10807909 | |
Introduction and hypothesis | dysuria, Dysuria | DISEASE | Dysuria is a common symptom present in several urological and gynecological conditions. Management relies on the underlying disease but may require additional symptomatic treatment. This study evaluated the combination of methenamine 250 mg and methylthioninium chloride 20 mg in the treatment of dysuria versus phenazopyridine. | PMC10756887 |
Methods | dysuria, pain | This was a multicenter, single-blind, randomized, superiority clinical trial, including individuals over 18 with dysuria and a score ≥ 5 points on the pre-treatment categorical scale for pain. The primary outcome was the proportion of participants presenting excellent clinical response within 24 h after treatment. Improvement up to 72 h, time to reach improvement, sustained healing, investigators’ opinion, and safety were also evaluated. | PMC10756887 | |
Results | dysuria, pain | Three hundred and fifteen participants were evaluated. Demographic characteristics and symptoms of dysuria were comparable between groups at baseline. The difference in the excellent response rate between treatments within 24 h was 12.7% (95% CI 6.16, 19.21) for pain, 9.4% (95% CI 3.32, 15.39) for burning, and 12.7% (95% CI 6.37, 18.99) for burning on urination, all in favor of the test drug, which was also superior from 36 to 48 h. Treatments were similar concerning time to reach the absence of symptoms and in the percentage of participants with sustained healing after 72 h. | PMC10756887 | |
Conclusions | dysuria | The association of methenamine with methylthioninium is superior to phenazopyridine in the treatment of dysuria. | PMC10756887 | |
Keywords | PMC10756887 | |||
Introduction | dysuria, Dysuria | GYNECOLOGICAL DISEASE | Dysuria is a symptomatic manifestation of several urological and gynecological diseases [Management of dysuria relies on the cause; discomfort relief may require additional symptomatic treatment. Phenazopyridine, formerly known as an antiseptic, is an analgesic widely used in urinary tract symptoms [In this study we hypothesized that the combination of methenamine 250 mg and methylthioninium chloride 20 mg is superior to phenazopyridine in the treatment of dysuria. | PMC10756887 |
Materials and methods | PMC10756887 | |||
Study design and ethics | This was a phase III, prospective, multicenter, single-blind, randomized, superiority clinical trial, conducted in four research centers in Brazil, between June 2016 and December 2017. The study was carried out in compliance with Good Clinical Practice, the International Council for Harmonization, and the Declaration of Helsinki and its amendments. The study protocol was approved by an independent local ethics committee (number 1.040.734), registered on | PMC10756887 | ||
Study population | primary kidney disease, fever, epilepsy, pain, dehydration, dysuria, kidney stones, liver or renal dysfunction, metabolic acidosis, depression, gout | URETHRAL STRICTURE, EPILEPSY, PYELONEPHRITIS, DEHYDRATION, KIDNEY STONE, UTI, METABOLIC ACIDOSIS, GOUT, NEUROGENIC BLADDER | Eligible criteria were participants of both sexes, aged 18 years and older, presenting dysuria with scores ≥ 5 points on the pre-treatment categorical scale for the pain symptom (seven-point scale: 1–2: absent; 3–4: mild; 5–6: moderate; 7: severe). Women of childbearing age and who were sexually active had to be using safe contraceptive methods and had to present a negative pregnancy test before inclusion.Participants were not included if they were pregnant or breastfeeding, had a history of sensitivity to any of the components of the test drug or comparator, presented fever (axillary T°: ≥ 38.5ºC) with dorsal or lumbar pain, kidney stones, urethral stricture, primary kidney disease, neurogenic bladder, or complicated UTI. Other exclusion criteria were deficiency of the enzyme glucose-6-phosphate-dehydrogenase, severe dehydration, metabolic acidosis or gout, pyelonephritis, use of serotonergic or antimicrobial drug within 7 days before the beginning of the study. Participants were also not included if they had any condition that prevented them from participating in the study because of health-related problems (epilepsy, depression, severe liver or renal dysfunction) or according to the investigators’ evaluation, as well as those who had participated in clinical study protocols in the last 12 months. | PMC10756887 |
Randomization, allocation, and blinding | Participants were randomized using a sequence generated by the Excel program with a blocking scheme in a 1:1 ratio, and treatment was available as per the randomization list. A biostatistician-validated randomization list of masked treatments was provided, and the allocation of the research participants was carried out sequentially in the order of inclusion in the study until the final number of evaluable participants was reached. To ensure blinding, the sponsor was responsible for randomization and distribution, and the medication was dispensed to the participant by a professional chosen by the principal investigator. Additionally, participants were instructed not to report to the investigators changes in urinary color or any product characteristic. | PMC10756887 | ||
Intervention | urinary bacterial infection | Group 1 received the investigational drug, consisting of the combination of methenamine 250 mg and methylthioninium chloride 20 mg (EMS, Hortolândia, Brazil), two tablets by oral route every 8 h for 3 days. Group 2 received the comparator, consisting of phenazopyridine hydrochloride 100 mg (Pyridium®, Zodiac), two pills via the oral route every 8 h for 3 days.Laboratory tests were carried out at the beginning and the end of the study and comprised blood count, biochemistry, urine analysis, and urine culture with antibiogram. Participants had two visits to the research center: V1 (beginning of treatment) and V2 (4 days ± 1). Adjuvant therapy was acceptable in the case of urinary bacterial infection confirmed by urine culture, with ciprofloxacin 250 mg (Proflox®; EMS) twice a day for 3 days, given at V2, and two extra visits were required: V3 (7 days ± 1) and V4 (12 ± 1). Those who used an analgesic during the study were excluded from the trial, and their data were analyzed only for safety. | PMC10756887 | |
Outcomes | dysuria, Dysuria, pain | ADVERSE EVENTS, SECONDARY | The primary outcome was the improvement of dysuria, evaluated as the percentage of participants presenting an excellent clinical response, defined as an improvement in symptoms from mild, moderate, or intense to absent, from 0 to 24 h after treatment.Dysuria was divided into three components: pain, burning, and burning on urination, and participants used the categorical seven-point scale and a 100-mm visual analog scale (“0” = absence of the symptom and “100” = maximum intensity) to report symptoms.The secondary outcomes were:Percentage of participants with an excellent clinical response at 12 h, 36 h, 48 h, and 72 hTime to reach absence of symptomsSustained healing—defined as the absence of pain after 72 hImprovement of dysuria by the investigator using the Clinical Global Impression (CGI) scale, which consisted of two subscales, the severity (CGI-S) and the improvement (CGI-I) [Urine culture at the end of the treatmentSafety, by the incidence of adverse events (AEs) | PMC10756887 |
Sample size calculation | dysuria | The sample size was calculated using a parallel design with two samples and a superiority test for proportions. We adopted a superiority margin of 1.85% based on studies evaluating the improvement of dysuria of phenazopyridine hydrochloride and placebo [ | PMC10756887 | |
Statistical analysis | dysuria | The analysis was carried out using the intention-to-treat (ITT) population, evaluating all participants who were included in the study after randomization, who received at least one dose of the medication, and who presented at V2.Demographic data were evaluated using descriptive analysis, presenting mean, median, standard deviation, minimum, and maximum if necessary.We calculated the percentage of participants presenting an excellent clinical response in 24 h for each group with the 95% confidence interval (CI), and the treatment with the test drug was considered superior to the comparator in symptomatic relief of dysuria if the lower limit of the 95% CI of the difference between groups was greater than the superiority margin.For categorical variables, a categorical change test, such as McNemar’s test, was applied to compare patients' notes (0 h, 12 h, 24 h, 48 h, and 72 h; comparison within each treatment). The Chi-squared test was used to test the significance of differences in proportions between drugs (test and comparator). The Kaplan–Meier method and the log-rank test assessed the time to relieve dysuria. Episodes of AEs were analyzed descriptively. | PMC10756887 | |
Primary outcome | dysuria, pain | Groups 1 and 2 showed statistically significant improvement in the three symptomatic components of dysuria within 24 h of treatment evaluated with the categorical scale. They were 15.19% in group 1 without pain, 12.03% without burning, and 15.19% without burning on urination versus 3.21%, 3.21%, and 2.56% in group 2 respectively (Table Evaluation of dysuria: pain, burning, and burning on urination within 24 hIn group 1, 16% of participants presented excellent clinical response for pain within 24 h, versus 3.31% in group 2. The difference between groups was 12.69% (95% CI 6.16, 19.21%). In the evaluation of burning, 12.67% of group 1 showed excellent clinical response, versus 3.31% in group 2, a difference of 9.36% (95% CI 3.32, 15.39%). 15.33% of group 1 showed an excellent clinical response in burning on urination versus 2.65% in group 2, a difference of 12.68% (95% CI 6.37, 18.99%). As the lower limit of 95% CI of the difference in the excellent response between the two treatments was greater than 1.85% in all components of dysuria, the test drug was superior to the comparator.The evaluation of primary outcome in the per protocol (PP) population showed similar results for the three components: pain (95% CI 6.63%, 20.66%), burning (95% CI 3.54%, 16.55%), and burning on urination (95% CI 6.87%, 20.43%). | PMC10756887 |
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