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Group VS | The video stylet (TRS K2, UE Medical Equipment Co., Ltd., Zhejiang, China, Fig. | PMC10512610 | ||
Group FV | The flexible videoscope (TIC, UE Medical Equipment Co., Ltd., Zhejiang, China, Fig. After successful tracheal intubation, the patient was connected to the anesthesia machine for mechanical ventilation, the tidal volume was adjusted to 10 ml/kg, and the respiratory rate 12 breaths/min to maintain PETCO | PMC10512610 | ||
Patient evaluation | The success rate of the first intubation was recorded as the primary observation. The level of glottic exposure (Wilson-Cormack-Lehane grading, W–C-L) [ | PMC10512610 | ||
Statistical analyses | To calculate the sample size, we performed a preliminary experiment with 20 patients in each group (60 patients in total), and the first-pass intubation success rate in each group was 75% in Group VL, 95% in Group VS, and 90% in Group FV. With The data were analyzed using SPSS 26.0 statistical software. Continuous variables, such as the basic characteristics of patients, are expressed as the mean ± standard deviation. Comparisons of measurement data were performed using the | PMC10512610 | ||
Discussion | ’s mouth, glottis, epiglottis | In this randomized parallel-group study, we showed that all three devices were ultimately effective for intubation, higher first-pass intubation success rates were obtained with the video stylet and the flexible videoscope. Endotracheal intubation with the video stylet resulted in shorter intubation time when compared with the video laryngoscope and flexible videoscope. Glottic exposure in patients with difficult airways is a major challenge when managing the airway, endotracheal intubation with flexible videoscope and video stylet having much better glottic exposure capabilities than video laryngoscope. Clearly, for the management of patients with difficult airways, video stylet and flexible videoscope perform much better.The increasing number of airway management devices that are being developed and used has changed the definition of a difficult airway [The video stylet does not require a large degree of mouth opening and head tilt and does not require the epiglottis to be lifted, which may effectively reduce the degree and force of instruments contacted with the oropharynx. Therefore, the damage to the oropharyngeal mucosa caused by intubation is reduced, which is an obvious advantage for intubation in patients with cervical bracing [The flexible videoscope has the advantage of not limiting the diameter of the tracheal tube and, due to the softness of its light-guiding hose, is also better than a regular video laryngoscope in terms of reducing damage to the patient’s mouth and airway during intubation. However, we found that its intubation time was longer than that of the video laryngoscope and video stylet, probably because the flexible videoscope light-guiding hose was difficult to fix during the operation and it was more difficult to operate. Additionally, because muscarinic drugs and gravity reduce tension in the epiglottis and tongue, an assistant sometimes was needed to tilt the head back and elevate the jaw to open the epiglottis and obtain a view of the glottis. Tracheal intubation using a fiberscope takes longer than that with an endoscope [This study has two limitations, as described below. Firstly, the criteria for recruiting subjects may not include all patients who meet the definition of a difficult airway. For example, in recent studies, supraglottic and subglottic ultrasound measurements or upper lip biting tests have been performed to predict a difficult airway [ | PMC10512610 | |
Conclusion | hypoxia | HYPOXIA | When managing the airway of patients with difficult airways, all three devices can be used to achieve high intubation success rates, but the video stylet and flexible videoscope provide a better view of the vocal cords and are superior to the video laryngoscope in terms of the first-pass intubation success rate. The use of a video stylet has the advantage of a relatively shorter intubation time, allowing successful intubation in a shorter time and reducing the patient’s hypoxia time. Therefore, when anesthesiologists faced with a difficult airway, a video stylet should be the first choice, and if the airway is still not under control, a flexible videoscope should be used. | PMC10512610 |
Acknowledgements | We acknowledge the assistance of American Journal Experts (AJE) for English language editing. | PMC10512610 | ||
Authors’ contributions | TZ and RHL designed the study and drafted the manuscript. PZ completed the anesthesia management. KYZ enrolled patients. All authors read and approved the final manuscript. | PMC10512610 | ||
Funding | This research was funded by the Research Fund Project at the Hospital Level of Luan Hospital, Anhui Medical University (2021kykt05). | PMC10512610 | ||
Availability of data and materials | The datasets used and/or analyzed during the current study were available from the corresponding author on reasonable request. | PMC10512610 | ||
Declarations | PMC10512610 | |||
Ethics approval and consent to participate | The present study was approved by the Ethics Committee of the Affiliated Luan Hospital, Anhui Medical University (NO. 2021LL005), and written informed consent forms were signed by all the participants or their relatives before enrollment. As part of our study, we adhere to established international standards, including the principles outlined in the Helsinki Declaration. The trial was retrospectively registered at the China Clinical Trials Registration Center ( | PMC10512610 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10512610 | ||
References | PMC10512610 | |||
Purpose | METASTATIC BREAST CANCER | PUFFIN (NCT02896855), a Chinese bridging study in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer, assessed consistency of efficacy and safety of pertuzumab plus trastuzumab and docetaxel versus placebo, trastuzumab, and docetaxel, with CLEOPATRA (NCT00567190). | PMC9883304 | |
Methods | Eligible patients, | PMC9883304 | ||
Results | Updated median PFS: 16.5 months (pertuzumab arm) and 12.5 months (placebo arm), with a hazard ratio (HR) of 0.60 [95% confidence interval (CI) 0.45, 0.81; | PMC9883304 | ||
Keywords | PMC9883304 | |||
Mathematics Subject Classification | PMC9883304 | |||
Introduction | diarrhea | ADVERSE EVENTS, METASTATIC BREAST CANCER, MUCOSAL INFLAMMATION, FEBRILE NEUTROPENIA | Pertuzumab and trastuzumab (PERJETAPertuzumab plus trastuzumab and docetaxel in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer was shown to improve progression-free and overall survival (PFS and OS) significantly compared with placebo plus trastuzumab and docetaxel in CLEOPATRA (NCT00567190). At CLEOPATRA’s primary analysis, independently assessed median PFS was 18.5 months in the pertuzumab arm and 12.4 months in the placebo arm. The PFS hazard ratio (HR) was 0.62 [95% confidence interval (CI) 0.51, 0.75; Exploratory analyses of safety showed a higher proportion of patients from Asia [China (including Hong Kong) plus Japan, Korea, the Philippines, Singapore, and Thailand] experienced adverse events (AEs) than patients from Europe, North America, and South America combined. The most common AE was febrile neutropenia, which the authors postulated may have been related to increased diarrhea and mucosal inflammation. Despite these differences, comparable survival benefits across regions were observed [PUFFIN (NCT02896855) was a Chinese bridging study to evaluate the efficacy and safety of pertuzumab and to determine consistency with CLEOPATRA. The primary analysis showed that efficacy data were consistent with CLEOPATRA. Median investigator-assessed PFS was 14.5 months and 12.4 months in the pertuzumab and placebo arms, respectively; OS was relatively immature. The PFS HR was 0.69 (95% CI 0.49, 0.99), which was similar to the investigator-assessed PFS HR in CLEOPATRA; 0.62 (95% CI 0.51, 0.75) [ | PMC9883304 |
Methods | HER2-positive | ONCOLOGY, DISEASE, METASTATIC BREAST CANCER, METASTATIC DISEASE | PUFFIN was a phase III, randomized, double-blind, placebo-controlled study conducted across 15 centers in China. The protocol was approved by the institutional review board at each participating site. Informed consent was provided from all participants. The study design, eligibility criteria, procedures, assessments, and statistical methods have been reported previously in the primary analysis [Eligible patients were aged ≥ 18 years with HER2-positive (centrally confirmed immunohistochemistry 3 + or in situ hybridization-positive), locally recurrent or metastatic breast cancer. Patients were eligible if they had not received prior treatment for metastatic disease (except for one hormonal regimen before randomization), no prior treatment with HER2-targeting therapies (except trastuzumab in the neoadjuvant or adjuvant settings) or tyrosine kinase inhibitors, and were disease-free for ≥ 12 months. Hormone receptor status was centrally confirmed. Further inclusion criteria included a left ventricular ejection fraction (LVEF) of ≥ 55% at baseline and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. Patients were eligible if they had measurable or non-measurable disease.Patients were excluded if they had prior exposure to doxorubicin of ≥ 360 mg/m | PMC9883304 |
Procedures | visceral disease | Randomization was 1:1, using visceral disease and hormone receptor status to stratify patients to pertuzumab (840 mg loading dose, followed by 420 mg every 3 weeks), trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks), and docetaxel (75 mg/mAfter the primary analysis, patients could cross over from the placebo arm to the pertuzumab arm due to pertuzumab showing a clinically significant improvement over placebo. | PMC9883304 | |
Statistical methods | PFS and OS were estimated using the Kaplan–Meier approach. HR and 95% CIs were estimated by a Cox proportional hazard model using the stratification factors. To compare the two arms, a two-sided stratified log-rank test was used. Statistical testing was considered exploratory. Safety analyses were descriptive. | PMC9883304 | ||
Results | PMC9883304 | |||
Study population | From 13 September 2016 to 28 September 2017, 243 eligible patients were randomized: 122 and 121 to the pertuzumab and placebo arms, respectively [Disposition of patients | PMC9883304 | ||
Progression-free survival | Updated median investigator-assessed PFS was 16.5 months (95% CI 12.7, 20.2) in the pertuzumab arm and 12.5 months (95% CI 10.4, 14.6) in the placebo arm (Fig. Investigator-assessed PFS in | PMC9883304 | ||
Overall survival | Median OS was not reached in either arm. The stratified HR was 0.68 (95% CI 0.45, 1.03; OS in | PMC9883304 | ||
Treatment exposure | Prior to crossover, the median number of pertuzumab or placebo cycles administered to patients was 22.0 (range 1–4) and 17.0 (range 1–68), over the respective median duration of 66.1 weeks (range 3–225) and 52.3 weeks (range 3–207). The median number of trastuzumab cycles in the pertuzumab and placebo arms was 22.0 (range 1–74) and 17.0 (range 1–74), respectively. Both arms had a similar median number of docetaxel cycles, with 7.0 (range 1–26) in the pertuzumab arm and 6.5 (range 1–22) in the placebo arm. The median dose of each was 900.0 mg and 826.1 mg. Following crossover, the median number of pertuzumab cycles was 6.0 (range 4–8), with a median duration of 18.1 weeks (range 12–24). | PMC9883304 | ||
Discussion | Leukopenia, pneumonia, neutropenia, diarrhea, leukopenia, febrile neutropenia, anemia, hypertension | LEUKOPENIA, PNEUMONIA, NEUTROPENIA, LEUKOPENIA, FEBRILE NEUTROPENIA, DISEASE, ANEMIA, HYPERTENSION | PUFFIN previously met its primary objectives, demonstrating consistency of efficacy with CLEOPATRA [Subgroup analyses showed consistency with the overall PFS and OS results. Compared with the primary PFS subgroup analysis, the final analysis showed an overall shift toward the pertuzumab group having improved PFS and OS, with little difference between disease type, hormone receptor status, and low or high HER2 status. Patients aged ≥ 65 years showed no difference in PFS between arms. Subgroup analyses showed that patients in the < 65 years age group [PFS HR = 0.58 (95% CI 0.43, 0.80) and OS HR = 0.60 (95% CI 0.39, 0.94)] had better outcomes with pertuzumab. Patients who were ≥ 2 years treatment-free had improved PFS over patients who were < 2 years treatment-free [HR = 0.43 (95% CI 0.25, 0.75) vs. HR = 0.67 (95% CI 0.36, 1.25)]. However, the OS subgroup analysis showed patients who were < 2 years treatment-free had improved OS over patients who were ≥ 2 years treatment-free [HR = 0.30 (95% CI 0.10, 0.92) vs. HR = 0.68 (95% CI 0.32, 1.46)]. Patients with de novo disease had poorer OS with pertuzumab compared with placebo [HR = 1.22 (95% CI 0.58, 2.59)]; this conflicts with CLEOPATRA [HR = 0.65 (95% CI 0.51, 0.82)], which showed that patients with no previous treatment had better prognosis with pertuzumab than with placebo [The overall safety profile was consistent with the primary analysis, with few AEs reported that required additional follow-up in either arm, and no new safety signals. Leukopenia remained the most common AE in the study, followed by neutropenia. Grade ≥ 3 AEs remained balanced between arms, with neutropenia, leukopenia, febrile neutropenia, anemia, and diarrhea being the most reported (with the addition of hypertension and pneumonia since the primary analysis). No new cardiac AEs were reported since the primary analysis. Comparing the safety profile to the Asian population in CLEOPATRA’s exploratory analysis, the rates of AEs of special interest to pertuzumab were lower, specifically diarrhea (45.9% vs. 74.4% vs.) and febrile neutropenia (4.1% vs. 25.6%) [ | PMC9883304 |
Conclusions | METASTATIC BREAST CANCER | This final analysis of PUFFIN showed, as with the primary analysis, that overall efficacy was consistent with that of the ITT population in CLEOPATRA. Safety of pertuzumab remained consistent with the known pertuzumab profile. Overall, PUFFIN contributes to the totality of data with pertuzumab in previously untreated HER2-positive locally recurrent or metastatic breast cancer and supports the favorable benefit–risk profile of pertuzumab in Chinese patients. | PMC9883304 | |
Author contributions | All authors contributed to drafting the work or revising it critically for important intellectual content and read and approved the final the version of the manuscript to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. BX designed the work and provided substantial contributions to the conception. All authors all contributed to the acquisition, analysis, or interpretation of data for the work. | PMC9883304 | ||
Funding | This work was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland (no grant number applicable). F. Hoffmann-La Roche Ltd was involved in the study design, data interpretation, and the decision to submit for publication in conjunction with the authors. | PMC9883304 | ||
Data availability | For eligible studies, qualified researchers may request access to individual patient-level clinical data through a data request platform. At the time of writing, this request platform is Vivli. | PMC9883304 | ||
Declarations | PMC9883304 | |||
Conflict of interest | WL, HL | BX reports institutional research funding (investigator fees for this study to his institution) from F. Hoffmann-La Roche Ltd; and consultant/advisory roles for Novartis, Roche, and AstraZeneca. WL, QZ, QL, XW, HL, TS, YY, HZhe, and JF all report institutional research funding (investigator fees for this study) from F. Hoffmann-La Roche Ltd. HZhu and HM are employees of F. Hoffmann-La Roche Ltd. AS is an employee of Roche Products Limited. AK is an employee of Roche Products Limited and holds stock in F. Hoffmann-La Roche Ltd. All authors received research funding in the form of third-party writing assistance for this manuscript, provided by F. Hoffmann-La Roche Ltd. | PMC9883304 | |
Ethics approval | ICH | This study was conducted in full conformance with the International Council for Harmonisation (ICH) E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The protocol, the informed consent forms, and any accompanying material provided to patients were submitted to the independent ethics committee (IEC) by the Principal Investigator and reviewed and approved before the study was initiated. A full list of the IECs at participating institutions is provided with the primary analysis [ | PMC9883304 | |
Consent to participate | Written informed consent for participation in the study had to be obtained before performing any study-specific screening tests or evaluations. Informed consent forms for enrolled patients and for patients who were not subsequently enrolled were maintained at the study site. | PMC9883304 | ||
Consent for publication | Not applicable. | PMC9883304 | ||
References | PMC9883304 | |||
Purpose | rUTI | RECURRENT URINARY TRACT INFECTION | To evaluate efficacy and safety of vaccination with StroVac compared to placebo in patients with recurrent urinary tract infections (rUTI). | PMC9870822 |
Material and methods | UTI, rUTI | BACTERIAL URINARY TRACT INFECTION, RECURRENCES, RECURRENCE, UTI | We performed a prospective, double-blinded, placebo-controlled study in patients with uncomplicated rUTI. Patients received three single intramuscular injections with StroVac every two weeks. Primary endpoint was the number of bacterial urinary tract infections (UTI) over 13.5 months after randomization and adjusted by the respective “baseline” value when comparing verum and placebo group. Secondary endpoints were the number of patients with non-recurrence, time to first recurrence, frequency of recurrences, and patients' self-assessment of quality of life using a validated questionnaire. | PMC9870822 |
Results | 376 patients were randomized to both groups between January 2012 and March 2015. Mean age was 44.4 years. Patients were mainly female (98.4%). In the StroVac group ( | PMC9870822 | ||
Conclusion | UTIs, rUTI | StroVac reduced the number of clinically relevant UTIs like in former studies but did not show statistically significant better results than the chosen placebo. Most likely, that was due to a, since confirmed, prophylactic effect of the chosen placebo itself. Therefore, placebo-controlled and double-blinded studies using a different ineffective placebo preparation are needed to determine the importance of StroVac in prophylaxis of rUTI. | PMC9870822 | |
Keywords | PMC9870822 | |||
Introduction | UTI, rUTI | DISEASE, URINARY TRACT INFECTIONS, UTI | Urinary tract infections (UTI) are a common disease affecting 11% of women worldwide at least once per year [StroVac offers a different approach consisting of 10 strains of inactivated uropathogens: six of Therefore, we conducted a prospective, multicentre, randomized, double-blinded and placebo-controlled study on efficacy and tolerability of StroVac in patients with rUTI. | PMC9870822 |
Patients and methods | ICH | This double-blinded, randomized and placebo-controlled phase IV study was conducted from January 2012 to March 2015 in 40 sites in Germany. This study was conducted in compliance with the ICH Guideline E6 (R1) on Good Clinical Practice and registered under EudraCT no. 2010-020882-25. Several ethic committees were involved, including a leading committee in Berlin and local ethic committees in regions with participating centres. | PMC9870822 | |
Study participants | lower urinary tract symptoms, malignancy, diabetes mellitus, rUTI, liver or renal insufficiency, systemic infectious disease, neurogenic bladder dysfunction, bladder or kidney stones, UTIs | DIABETES MELLITUS, CONCOMITANT DISEASE, NEUROGENIC BLADDER DYSFUNCTION, UTI, SYSTEMIC INFECTIOUS DISEASE, COMPLICATIONS | Patients of both sexes aged 18–80 years were included if they had at least five symptomatic uncomplicated bacterial UTIs within 12 months prior to study inclusion. In accordance with current literature, UTI diagnosis required a positive urine culture with ≥ 10Exclusion criteria comprised complicated UTI, lower urinary tract symptoms due to other reasons than UTI, neurogenic bladder dysfunction, bladder or kidney stones, residual urine, pregnancy, acute systemic infectious disease, a malignancy in the recent 5 years or radiation therapy of the abdomen (without time limit) or any other body part within the last 5 years, malfunction of immunity due to concomitant diseases such as diabetes mellitus with unstable metabolic status, liver or renal insufficiency, or complications caused by presently used medications. Further exclusion criteria were therapy with StroVac any time prior study inclusion, therapy with antineoplastic agents five years prior study inclusion, therapy with Uro-Vaxom 3 years, instillation therapy 18 months and continuous antibiotic treatment (> 30 days) or postcoital antibiotic treatment six months prior study inclusion. During the time of this study in 2012–2015, D-mannose was not used as prophylactic therapy of rUTI and therefore not permitted. During the study period, concomitant therapy with the above mentioned substances was permitted as well, only antibiotics in case of a necessary treatment of a UTI were allowed. | PMC9870822 |
Endpoints | bacterial UTIs, UTIs | RECURRENCES, RECURRENCE | The primary endpoint was the number of bacterial UTIs over 13.5 months after randomization adjusted by the respective “baseline” value (ITT-population) when comparing verum and placebo group. Baseline adjustment was done by including the respective baseline value as covariate into the statistical model. Secondary endpoints were defined as the number of UTIs within 12 months observation period (visits V5–V9), number of patients with non-recurrence during the entire study period, time to first recurrence, and frequency of recurrences during the first 6 months vs. months 7–12 after finalisation of the immunization scheme. Furthermore, patients' self-assessment and quality of life were measured using a validated questionnaire compiled from EUROHIS-QOL-Score [ | PMC9870822 |
Study medication | The investigational medicinal products consisted of a basic suspension and a dry substance for preparing the suspension for injection. Finished verum suspension for one injection contained at least 10 | PMC9870822 | ||
Statistical analysis | UTIs | RECURRENCES, RECURRENCE | The sample size calculation was based upon an average of 6.2 UTIs in the year pre-study, a 50% placebo response and an additional 15% StroVac effect in reducing UTIs during the study period. The number of 6.2 UTIs was calculated from data of an earlier study [The efficacy analyses were performed using the intention to treat (ITT) population. The safety evaluable population (SEP) was used for safety analysis. The primary endpoint was evaluated in an approach for testing the superiority of StroVac over placebo. The statistical test was performed using the generalized linear model. The number of recurrences was analysed analogously, the time until first recurrence was calculated using Kaplan–Meier life-tables. The difference between the treatment groups was analyzed by the log-rank test. Statistical analyses were carried out by Pharmalog– Institut für Klinische Forschung GmbH, München using SAS-System version 9.2, SAS Institute Inc. | PMC9870822 |
Results | UTIs, rUTI | RECURRENCES, RECURRENCE, UTI | Of the 412 patients screened for eligibility, 376 patients were randomized equally to both groups between January 2012 and March 2015 (i.e. 188 patients per group, see Table Characteristics of patients with rUTI under prophylaxis with StroVac or placeboThe Results are presented as: mean and standard deviation (SD) and number and percent [In the StroVac group, confirmed UTIs were reduced from an average of 5.5 within 12 months prior to study enrolment to 1.2 UTIs in the 13.5 months following first injection. Apparently, the placebo group showed similar results with a reduction from 5.4 UTIs to 1.3 UTIs. Therefore, a statistically significant difference in the primary endpoint (UTI recurrences) was clearly missed (Summary of resultsUsed for calculation was the analysis set ITTPatients with non-recurrence after visit 5 in StroVac and placebo group. 86 of 188 patients after StroVac (46.0%) and 97 of 188 patients (51.6%) after placebo experienced no recurrence twelve months after study inclusion ( | PMC9870822 |
Subgroup analysis | cystitis, UTIs | RECURRENCES, CYSTITIS, UTI | In premenopausal women, no statistically significant difference was seen between the two treatment groups in the frequency of recurrences (In patients older than 70 years, the reduction of frequency of UTI (by 4.4–4.5 UTIs, Using a broader UTI definition (patients with self-documented UTIs without visiting a doctor, with monosymptomatic bacterial urinary tract infections, or with clinical cystitis without positive pathogen detection), a post-hoc subgroup of ITT patients who had more than 7 UTIs in the 12 months prior to randomization was analyzed. In this subpopulation ( | PMC9870822 |
Patient-reported outcomes/quality of life questionnaires (QoL) | UTI | In the StroVac group, complaints recorded in most QoL questionnaires were reduced by approximately 50% from V1 (baseline) to V9, in parallel to the reduction of UTI frequency. The mean scores of “symptom burden”, "mental consequences", and "effect on daily life" declined from 21.2 to 10.2, from 11.8 to 5.9, and from 9.7 to 4.4 points, respectively. But as the reduction in UTI frequency was similar in both treatment groups, no significant differences were observed in QoL as well. Even though statistical significance was nearly reached in the “mental consequences" score ( | PMC9870822 | |
Safety results | pyrexia, influenza-like illness, nasopharyngitis, pain | ADVERSE EVENTS, EVENT, INFLUENZA-LIKE ILLNESS, NASOPHARYNGITIS | Overall, 619 adverse events (AE) occurred within the treatment period, 426 AEs in the StroVac group in 115 patients (62.2%), and 193 AEs in 83 patients in the placebo group (44.1%). By the end of the study, most AEs had resolved (98.7%). Most AEs were mild (54.9%) and moderate (33.4%) in intensity, and 11.6% were classified as severe. Most severe AEs occurred in the StroVac group (55 vs 17 AEs). Most common AEs were vaccination site pain (37.2% in the StroVac group and 5.3% in the placebo group) and influenza-like illness (11.7 and 4.8%, respectively). Most common severe AEs were vaccination site pain, pyrexia and influenza-like illness as well. 63.3% of patients with AEs reported in the StroVac group, and 17% of patients in the placebo group were classified as having drug-related AEs. 88.6% of the patients assessed the tolerability of StroVac as “very good” and “good”.In the observation period after drug administration, 471 AEs occurred, equally in both groups showing 227 AEs in 81 patients in the StroVac group, and 244 AEs in 84 placebo patients. Again, most AEs were mild or moderate, severe AEs were more common in the placebo group. The most commonly reported event was nasopharyngitis (4.8 and 4.3% of all AEs in the StroVac and placebo group, respectively) followed by influenza-like illness (5.3 and 3.7%, respectively). Of all AEs, 2.7% were classified as drug-related in the StroVac group and 1.1% in the placebo group. Again, the majority of AEs had resolved by the end of the study. | PMC9870822 |
Discussion | StroVac reduced rUTI, urinary tract infections, fever, rUTI, UTIs | RECURRENCE, URINARY TRACT INFECTIONS, PERTUSSIS, FLU-LIKE ILLNESS, UTI, HEAT | Due to the emerging possibilities in non-antibiotic prophylaxis and a growing body of evidence proving their efficacy [Since the aim of the study was to prove the efficacy of StroVac in prophylaxis of rUTI, one has to state, that our study showed no significant advantage of StroVac over the placebo we used. We even saw a longer time till first recurrence and a higher rate of women with no UTI in the placebo group, even though not reaching statistical significance. But in spite of the failed statistical significance, StroVac reduced rUTI in patients with at least 5 UTI per year prior to prophylaxis to 1.0 UTI during follow up of 12 months. Overall, 71.7% of StroVac patients had only one or no UTI in the 12 months following the prophylactic injections.These results are in accordance with the existing literature. In the largest non-interventional trial on StroVac published until today with over 1200 patients, the authors found a reduction from 3.5 UTIs in 6 months before to 0.6 UTIs in the 6 months following therapy [When looking at other non-antibiotic prophylaxis regimens, similar results are described. Though, Wagenlehner et al. [This placebo-controlled study confirmed that vaccination with StroVac leads to the expected effect in reducing rUTI frequency clinically relevantly but not statistically significantly better than placebo. The flaw in our study was the placebo preparation we used. Because the placebo achieved a 1.5 times higher effect than was expected, the preparation utilized in our study was further investigated for possible beneficial qualities. Indeed, the analysis revealed an antibacterial effect of the placebo itself [Furthermore, the question remains, which definition of rUTI should be used in future studies. Since the study was conducted mainly in Germany, we used the definition provided by the German guidelines for recurrent uncomplicated urinary tract infections as established in 2010 [Lastly, since using heat activated bacterial strains, it is worth mentioning that we had only mild rates of reactions such as fever and flu-like illness, but despite the rate of 62.2% of AE in the StroVac group, 88.6% of the patients assessed the tolerability of StroVac as “very good” and “good”. This shows good tolerability and acceptance of the vaccine in patients. Even though comparable vaccines like whole cell pertussis vaccine showed high rates of AE, tolerability and safety in our study is supported by large studies on StroVac in Germany showing similar results [Nevertheless, the obvious remaining limitation of our study is the failure to show a statistically significant superiority over the placebo effect. On the other hand, we believe that our work was a well-designed randomized and double-blinded trial with a large and well-balanced patient cohort. Thus, we consider our study an important contribution to research on non-antibiotic prophylaxis of rUTI providing confirmation of the clinically relevant prophylactic effects of StroVac in rUTI. | PMC9870822 |
Author contributions | SP and AHH designed the study, SN wrote the manuscript with input from CP, AHH, WV, WF and AN, AN and SN edited the manuscript. | PMC9870822 | ||
Funding | This research was performed under funding of Strathmann GmbH & Co. KG. | PMC9870822 | ||
Declarations | PMC9870822 | |||
Conflict of interest | FABRY | S Nestler works as an advisor/author for Dermapharm, Strathmann, Abbvie, GlaxoSmithKline. S Peschel and AH Horstmann are employees of Strathmann GmbH & Co. KG. W Vahlensieck works as advisor/author for Apogepha, Bene, Bionorica, Strathmann, Fresenius, Infectopharm, Medice, Perrigo, Repha. W Fabry have no conflicts of interest. A Neisius works as an advisor/author for MSD, Janssen, AstraZeneca, Ispen, Amgen, Roche, GlaxoSmithKline, Optimed, Boston Scientific. | PMC9870822 | |
Ethical approval | ICH | This study was conducted in compliance with the ICH Guideline E6 (R1) on Good Clinical Practice and registered under EudraCT no. 2010-020882-25. Several ethic committees were involved, including a leading committee in Berlin and local ethic committees in regions with participating centres. Informed consent was obtained by all patients. | PMC9870822 | |
References | PMC9870822 | |||
Subject terms | CKD | SECONDARY | We investigated the effect of two dosing regimens of oral iron on iron status and hematological parameters in patients with CKD. In this single center, open label, randomized, active controlled clinical trial, stable adult patients with CKD stage G3–4 with percentage transferrin saturation (%TSAT) ≤ 30% and serum ferritin ≤ 500 ng/ml were eligible. Participants were randomized to receive either 100 mg of ferrous ascorbate once daily (OD group) or 100 mg of ferrous ascorbate twice daily (BD group, total daily dose 200 mg). The primary outcome was change in %TSAT between groups over 12 weeks. The secondary outcomes were changes in other iron status and hematological parameters, serum interleukin-6 (IL-6) and hepcidin. 80 participants were enrolled out of which 76 completed the study. Change in %TSAT was not significantly different between groups (β = − 1.43, 95% CI − 3.99 to 1.12, BD group as reference). The rise in serum ferritin was less in the OD group as compared to BD group (β = − 0.36, 95% CI − 0.61 to − 0.10) whereas MCHC increased in the OD group as compared to decrease in the BD group (β = 0.37, 95% CI 0.067–0.67). These observations need exploration to ascertain the impact of different oral iron dosing strategies in CKD. | PMC9813132 |
Introduction | Anemia, CKD, chronic kidney disease, CVD | CVD, ANEMIA, CARDIOVASCULAR DISEASE | Anemia is common in chronic kidney disease (CKD) and has been associated with impaired quality of life, cardiovascular disease (CVD) and mortalityIn patients with CKD who are not on dialysis, oral route may be preferred as initial mode of iron supplementation. Oral iron is inexpensive, self-administered, convenient and easily available. The dosing frequency varies from once a day to 2–4 times a day depending on type of preparation | PMC9813132 |
Methods | PMC9813132 | |||
Study design | The study was a single centre, pilot study. It was parallel arm, randomized, open label, active controlled, interventional trial conducted at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. The trial was approved by the Institute Ethics Committee of PGIMER, Chandigarh and prospectively registered at the Clinical Trials Registry of India ( | PMC9813132 | ||
Study population | TSAT ≤, CKD | All adults with a diagnosis of CKD stage G3–4 attending the outpatient clinic at PGIMER were eligible for screening. Subjects between the ages of 18 and 70 years, TSAT ≤ 30%, serum ferritin ≤ 500 mg/L | PMC9813132 | |
Enrolment and randomization | At enrolment, all participants entered 2-week run-in period. This was done to ensure clinically stable status of participants. The visit scheduled after completion of run-in period was referred to as baseline visit. Participants were randomized in 1:1 allocation ratio to either of the two study groups at baseline visit. The randomization scheme was generated from the website | PMC9813132 | ||
Intervention and follow up | ADVERSE EVENTS | Participants were randomized to oral iron supplementation with ferrous ascorbate in either once daily (100 mg of elemental iron once daily i.e., 100 mg total daily dose, referred to as OD group) or twice daily (100 mg elemental iron twice daily i.e., 200 mg total daily dose, referred to as BD group) dosing for 12 weeks. They were instructed to take drug empty stomach at least 1 h prior to the meals. Participants were scheduled for follow up visits at 2, 5 and 12 weeks after baseline visit. Participants were deemed compliant if they had taken > 90% of the dispensed doses. Participants were encouraged to report any change in their health status till 2 weeks after completion of study period. All adverse events were recorded. Fasting blood samples were collected at baseline, 2 weeks, 5 weeks and 12 weeks. Samples collected at baseline and 12 weeks were also processed for storage at − 80 °C. | PMC9813132 | |
Outcomes | hypochromic red blood cells | SECONDARY | The primary outcome was difference in change in % TSAT over 12 weeks between the two groups. The secondary outcomes were differences in changes in serum ferritin, blood hemoglobin concentrations, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), percentage of hypochromic red blood cells (% HYPO-He), reticulocyte hemoglobin equivalent (RET-He), serum interleukin-6 (IL-6) and serum hepcidin concentrations over 12 weeks between the groups. | PMC9813132 |
Measurements | BLOOD | All measurements were done in fasting blood samples. Blood hemoglobin concentrations, MCH, MCV, MCHC, % HYPO-He and RET-He were measured at every visit on Sysmex XN-1000™ Hematology Analyzer (Sysmex Corporation, Kobe, Japan). These measurements were done within 4 h of sample collection. % TSAT concentrations were calculated from serum iron | PMC9813132 | |
Statistical considerations | SD | REGRESSION, SECONDARY | Assuming dropout rate of 10%, a sample size of 80 participants (40 in either group) was required to detect absolute difference of 3% in % TSAT [standard deviation (SD) ± 4.5%] between the two groups with 80% power and two sided α of 0.05. All participants with non-missing outcome data were included in the analysis. Descriptive statistics were used to describe characteristics of study participants. Data were presented as mean ± SD or median (interquartile range, IQR) as appropriate. For baseline measurements, continuous variables were compared by independent sample t test if normally distributed, or Mann–Whitney U test if distribution were skewed. Categorical variables were analyzed by Chi-squared test or Fisher exact test as appropriate. We used linear mixed effect model as primary analysis to assess the difference in change in concentrations of primary and secondary outcomes over the study period between the 2 groups. Group (OD and BD), follow up time (week), sex and baseline concentration (value) were defined as fixed effects and study participants as random effects. Simple linear regression was modelled for those parameters which were measured at baseline and 12 weeks (IL-6 and hepcidin). P-values < 0.05 were considered statistically significant. Logarithmic transformation was used before fitting linear mixed effects model or simple linear regression model for following parameters: serum ferritin, %HYPO-He, TIBC, serum IL-6 and serum hepcidin. | PMC9813132 |
Ethics approval and consent to participate | Study was approved from the Institute Ethics Committee and patients were enrolled in this study after getting the written consent prior to study procedures. | PMC9813132 | ||
Change in iron status and hematological parameters in the study population | Serial measurements done at 2, 5 and 12 weeks in both the groups are shown in Supplementary Tables | PMC9813132 | ||
Adverse events and others | ADVERSE EVENTS | All participants who completed study were compliant with study medication. Minor adverse events were recorded during the study (Supplementary Table | PMC9813132 | |
Discussion | iron deficiency anemia, CKD, TIBC | IRON DEFICIENCY ANEMIA, IRON DEFICIENCY, SECONDARY | In our study, the changes in %TSAT, serum iron and TIBC did not differ significantly between OD and BD dosing groups over 12 weeks. However, serum ferritin increased significantly in the BD group as compared to the OD group. Either repletion of intracellular stores or sequestration of iron within the cellular stores will lead to rise in serum ferritin concentrations. Overall, in the study population, serum hepcidin concentrations increased significantly over 12 weeks though there was no difference between the groups. This is in line with expected biological response in hepcidin concentrations to oral iron supplementation and repletionAt 12 weeks, MCHC increased in the OD group as compared to decrease in the BD group. It is not surprising that the change in MCHC was not statistically significant when overall study population was considered as the directions of change between the groups were opposite. MCHC is a calculated value and expressed in g/dL as a ratio of hemoglobin to hematocrit. It represents the average concentration of hemoglobin per unit of volume of red blood cell (RBC). MCHC has been traditionally regarded as a reliable marker of availability of iron within the preceding 3–4 months and its incorporation in intracellular hemoglobinWith iron repletion, changes in MCV and hemoglobin lag changes in hemoglobin content within RBCs as reflected by MCH and MCHCOur study has several strengths. The study was a randomized, controlled trial. We did serial measurements at baseline, 2, 5 and 12 weeks on the same platform. We selected participants according to the prevalent KDIGO clinical practice guideline, which is more aligned with practice. We have excluded patients who would have required erythropoietin therapy or would have been at risk of poor iron absorption or iron loss from gut. However, lack of a placebo arm, open-label design, restriction to single center and short duration of follow up are few limitations of our study. We have also not measured other biomarkers of iron deficiency like serum soluble transferrin receptor. Also, wide entry criteria with respect to iron status and already higher hemoglobin levels at baseline might have led to limited hemoglobin response in the study population.In our study, we did not find any significant difference in %TSAT between the groups. Differences in secondary outcomes like ferritin or MCHC between groups are just hypothesis generating. These observations need to explored in patients with more objectively defined true or functional iron deficiency so that effects of less frequent oral iron dosing on long term clinical end points in patients with iron deficiency anemia and CKD can be uncovered. | PMC9813132 |
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-022-26589-x. | PMC9813132 | ||
Acknowledgements | We are thankful to Junior Laboratory Technicians: Ms Kiran Khere and Mr Nand Lal in the Department of Paediatrics at PGIMER, Chandigarh for their help in carrying out the study. | PMC9813132 | ||
Author contributions | P.K. | Conceived and designed the work: S.V., K.V., P.B., S.M.; data acquisition (screening, enrolment, and follow-up of patients): V.S., K.V., R.R., M.R., H.S.K., K.L.G., T.S. and S.K.S.; laboratory measurements: P.B., P.K., K.K. and A.K.Y.; data analysis: K.K., M.K., A.G., K.V., A.K.Y.; manuscript: K.V., V.S., A.K.Y., P.B., V.J. All authors have read and approved the manuscript. | PMC9813132 | |
Funding | This study was funded in-part through grant received by VJ from Department of Biotechnology, Ministry of Science and Technology, India (Grant No. BT/PR11105/MED/30/1345/2014). The funding agency had no role in design and conduct of this study. | PMC9813132 | ||
Data availability | The datasets analysed during this study are available from the corresponding author on reasonable request. | PMC9813132 | ||
Competing interests | VJ has research grants from Baxter, GSK and reports Consultancy and Advisory Board honoraria from Baxter Healthcare, and AstraZeneca, outside the published work. All other authors reported no conflict of interest. | PMC9813132 | ||
References | PMC9813132 | |||
Introduction | Eating disorders, Bulimia nervosa, psychosomatic disorders, Anorexia nervosa, AN | Eating disorders (EDs) including Anorexia nervosa (AN) and Bulimia nervosa (BN) are severe psychosomatic disorders with lifetime prevalence among females ranging from 2–4% [EDs can be treated in a variety of treatment settings. Different treatment settings offer varying degrees of treatment intensity and treatment structure, which may influence treatment effectiveness and costs. However, there is little empirical guidance as to what is the most appropriate treatment setting for an individual patient [Several clinical guidelines exist to guide treatment decisions for EDs [As the results of randomized controlled trials (RCTs) may not always directly map the real-world situation, more outcome research in routine clinical care is needed [The present study aimed to examine patient characteristics, treatment characteristics, and short-term outcomes among women suffering from AN or BN, who were treated with CBT-based interventions according to national clinical practice treatment guidelines in nine different treatment institutions in Germany and Switzerland. The following research questions were examined: What are the differences between patients admitted to full-time treatment and patients admitted to ambulatory treatment? How much treatment and which treatment components do patients with EDs typically receive within three months after treatment initiation? Are there differences between full-time treatment and ambulatory treatment? What are short-term outcomes of guideline-based cognitive-behavioral interventions conducted in routine clinical care among patients with EDs? Which variables are associated with symptomatic improvements? | PMC10313003 | |
Materials and methods | PMC10313003 | |||
Participants and procedure | Data were drawn from a large clinical trial [ | PMC10313003 | ||
Overview of study. | Sixty-four patients with AN and 66 patients with BN were enrolled in the study. Fifty-nine patients with AN and 57 patients with BN participated. Potentially eligible patients who were voluntarily admitted between July 2014 and April 2017 to cooperating treatment centers were approached by staff members and informed about the clinical study. Study eligibility criteria included female gender, age between 18 and 35 years, and a primary diagnosis of AN or BN. Exclusion criteria were current pregnancy, breast feeding, or intake of beta-blockers. Patients were assessed after treatment admission and three months later. Assessments included a clinician-administered diagnostic interview (60–90 minutes) and a self-report questionnaire (60 minutes). | PMC10313003 | ||
Cooperating sites and treatment | psychiatric | The study sites included nine treatment sites in western Germany and northern Switzerland, which provided CBT-based interventions in accordance with the national clinical practice treatment guideline for the treatment of ED [Full-time treatment consisted of 24/7-care in a medical or psychiatric hospital or a privately governed non-hospital treatment facility, provided by a multidisciplinary team, including individual and group therapy, nutritional counselling, meal support, and occupational/recreation therapy. Ambulatory treatment typically consisted of one or two sessions of individual psychotherapy per week provided by a psychotherapist. It should be noted that the number of treatment sessions for ambulatory patients was restricted by procedural standards of the German health care system. At the time of the study, health insurance companies in Germany only reimbursed a maximum of five ambulatory treatment sessions (probatory/diagnostic sessions). To continue treatment, health insurance policies required a report, which was evaluated in a peer review process before approval of the reimbursement of treatment costs was granted. This procedure typically resulted in a treatment break of 4–6 weeks, with no contact between the patient and the therapist. Patients’ insurance companies covered the treatment costs and admission to treatment was voluntarily.Treatments in all sites were conducted as usual. All sites confirmed that their treatment standards adhere to current clinical practice guidelines for the treatment of ED [ | PMC10313003 | |
Measures | PMC10313003 | |||
Diagnostic interview | DISORDERS | A clinician-administered, semi-structured diagnostic interview (DIPS; Diagnostic Interview for Mental Disorders) [ | PMC10313003 | |
Self-report questionnaire | Eating Disorder | PATHOLOGY | At pre- and post-measurement, all patients completed an online questionnaire including questions regarding age, education, nationality, relationships status, use of psychopharmaceutics, and number of cigarettes smoked per day. Symptoms of ED pathology were assessed by the global score of the Eating Disorder Examination Questionnaire (EDE-Q) [ | PMC10313003 |
Body-Mass-Index (BMI) | At pre- and post-measurement, weight and height of study participants were measured using a calibrated electronic scale (Seca 899, Basel, Switzerland) and a stadiometer (Seca 213, Basel, Switzerland). BMI was calculated as weight in kilograms divided by height in meters squared. | PMC10313003 | ||
Remission rates | weight gain | REMISSION | Patients were considered fully remitted if they met the following criteria: a) Full remission based on diagnostic interview (i.e., after full criteria for AN/BN were previously met, none of the criteria have been met for a sustained period of time), b) BMI ≥ 18.5 and c) EDE-Q global score ≤ 2.77. Patients were considered partially remitted if they met the following criteria: Partial remission based on diagnostic interview (i.e., for AN: after full criteria for AN were previously met, criterion A (low body weight) has not been met for a sustained period of time, but either criterion B (intense fear of gaining weight or becoming fat or behavior that interferes with weight gain) or criterion C (disturbances in self-perception of weight and shape) is still met; for BN: after full criteria for BN were previously met, some but not all, of the criteria have been met for a sustained period of time) and b) BMI ≥ 18.5. Remission rate criteria were based on definitions of previous studies [ | PMC10313003 |
Treatment intensity and treatment characteristics | To examine treatment intensity and treatment characteristics, brief online questionnaires were administered to therapists at post-measurement. Items assessed the number of individual and group sessions as well as treatment components and treatment goals discussed with patients (a list of response options was provided). The response rate of therapists was 67%. Patients received a similar brief online questionnaire. The response rate of patients was 77%. | PMC10313003 | ||
Statistical analyses | Statistical analyses were conducted using SPSS 27 (IBM). To describe the total sample as well as subsamples by diagnosis (AN vs. BN) and setting (full-time treatment vs. ambulatory treatment), means, standard deviations, frequencies, and percentages of measured variables were reported. Statistical comparisons between groups on several related continuous variables were based on multivariate analyses of variance. Statistical comparisons of categorical variables were based on chi-square tests. All comparisons were made at the level of p < .05. To examine symptomatic changes on ED-related variables, Cohen’s | PMC10313003 | ||
Results | PMC10313003 | |||
Descriptive characteristics of patients | On average, patients with EDs were 22.8 years (Descriptive characteristics of patients between treatment settings are also displayed in | PMC10313003 | ||
Treatment components and treatment goals reported by patients and therapists three months after treatment admission. | Anorexia Nervosa, Bulimia Nervosa | Note: Treatment may continue after the three-months post-measurement (particularly among ambulatory patients).* Only assessed among patients with AN. AN = Anorexia Nervosa. BN = Bulimia Nervosa. | PMC10313003 | |
Descriptive statistics of treatment received within three months after admission (therapist-report). | Anorexia Nervosa, Bulimia Nervosa | Note: Treatment may continue after the three-months (particularly among outpatients). AN = Anorexia Nervosa. BN = Bulimia Nervosa. | PMC10313003 | |
Symptomatic changes (means, standard deviations, Cohen’s | Anxiety, Bulimia Nervosa, Anorexia Nervosa, Depression, Eating Disorder | Note. Amb. = Ambulatory, AN = Anorexia Nervosa, BN = Bulimia Nervosa, BMI = Body-Mass-Index, EDE-Q = Eating Disorder Examination Questionnaire, BDI = Beck Depression Inventory, BAI = Beck Anxiety Inventory, SOMS = Somatic Symptoms Scale. M = mean, SD = standard deviation, n = sample size, d = Cohen’s d. Descriptive statistics are reported only for patients with complete outcome data (complete-case analysis). | PMC10313003 | |
Correlates of symptomatic improvements | weight gain | Among women with AN, a significant correlation was found only between weight gain and ED severity ( | PMC10313003 |
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