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Laboratory testing and toxicity monitoring. | toxicity, Hepatitis, Toxicity | ADVERSE EVENT, ALLERGY, HEPATITIS | All patients underwent medical interview, physical exam, and laboratory testing at all visits to monitor for safety. Laboratory testing for toxicity monitoring (complete blood counts, serum chemistries, and quantitative immunoglobulins) was performed at each visit prior to OFC by the Johns Hopkins Core Pathology Laboratory. Adverse event determinations were made using the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Hepatitis serologies were also performed at visit 1. Before the start of the food challenges, laboratory quantification of total IgE and specific IgE to peanut and peanut components were performed using the Phadia ImmunoCAP platform by the Johns Hopkins Dermatology, Allergy, and Clinical Immunology Reference Laboratory. The lower limit of detection for the Phadia system is 0.1 KUA/L for all specific IgEs. | PMC10425211 |
Statistics. | EVENT | All null hypothesis significance tests were 2-tailed. Normality testing was performed on all data using the Shapiro-Wilk test (α = 0.05). In the event that data did not demonstrate normal Gaussian distribution, nonparametric tests were utilized as described. For tests using multiple comparisons, corrections for multiplicity were employed as described, and only the All patients who received acalabrutinib (Sample size was determined pretrial based on the primary outcome. It was estimated that 10 subjects allowed for 80% power to detect a 3-fold increase (1.1 natural log units; i.e. 1 food-dose escalation) in the threshold food dose using a paired Because most patients tolerated the highest cumulative amount of peanut during food challenge after acalabrutinib treatment, the primary outcome was analyzed as a censored variable after trial using a Wilcoxon matched-pairs signed rank test with For symptom scores, 2-way RM ANOVA with Geisser-Greenhouse correction was used to determine the interaction between treatment (baseline versus acalabrutinib), food challenge dose, and the patient on total symptom scores at each food challenge dose and an interaction effect of treatment by challenge dose. Once a patient displayed an objective clinical reaction, symptom scoring was ceased. For statistical analysis only, the final symptom score value was duplicated for the remainder of (unconsumed) food doses in order to perform ANOVA. This adjustment is not reflected in the graph in Due to nonnormal distribution of skin puncture testing data, the significant interaction effect between treatment and extract dilution, and that many skin tests showed no wheal response at lower concentrations of peanut extract, skin test size to undiluted peanut extract was analyzed separately using a Wilcoxon matched-pairs signed rank test. The highest nonreactive skin test was also analyzed using a Wilcoxon matched-pairs signed rank test (Because the interaction effect between treatment and extract dilution was significant, and at lower concentrations of extract many basophil activation responses were 0, peanut extract dilution responses were analyzed using the AUC. The mean response for each patient across all peanut extract dilutions was calculated and analyzed using Wilcoxon matched-pairs signed rank test to compare baseline to acalabrutinib treatment. This mean height was not multiplied by width given that the peanut extract has only relative units (w/v). Peanut response means were graphed as AUC. This test was also used to compare responses to anti-IgE and fMLP.To analyze peanut- and peanut component-specific IgE values, a 2-way RM ANOVA with Geisser-Greenhouse correction was used to determine interaction between treatment (baseline versus acalabrutinib), peanut (or component), and patient on the level of specific IgE. Multiplicity-Other laboratory values obtained for safety analysis were analyzed with 1-way ANOVA with the Geisser-Greenhouse correction when applicable (for serum chemistries and quantitative immunoglobulins), and otherwise were analyzed with a mixed-effects analysis (for complete blood counts). | PMC10425211 | |
Study approval. | This trial was conducted under the approval of a United States Food and Drug Administration (FDA) Investigational New Drug application (IND 142734) and the Johns Hopkins University IRB (IRB00223615). Written informed consent was obtained from all patients prior to participation in study procedures. | PMC10425211 | ||
Data availability. | The data that support the findings of this study including the supplemental materials are available in a separate supporting data file available online. Further study-related human subject data is available from the corresponding author upon request and will be deidentified before sharing. | PMC10425211 | ||
Author contributions | MCD | RECRUITMENT | The trial was conceived of and designed by MCD and BSB. RVS and MCD oversaw the conduct of the trial and took lead roles in all aspects of study visits and patient care. Patient recruitment and screening was done by RVS. RAW assisted in patient recruitment. Collection of data was performed by MCD, RVS, CD, and DWZM. Data analyses were conducted by MCD and DV. The manuscript was written by RVS and MCD. All of the authors had access to the data and vouch for its completeness and accuracy and for fidelity to the protocol. All contributing authors were involved in review and final approval of the manuscript. | PMC10425211 |
Supplementary Material | PMC10425211 | |||
Supplemental data | PMC10425211 | |||
ICMJE disclosure forms | PMC10425211 | |||
06/29/2023 | In-Press Preview | PMC10425211 | ||
08/15/2023 | Electronic publication | PMC10425211 | ||
Schematic representing study design and patient disposition. | Flow diagram summarizing the ( | PMC10425211 | ||
Maximum tolerated peanut dose and symptom scores during OFC. | ( | PMC10425211 | ||
Secondary outcomes. | ( | PMC10425211 | ||
Baseline characteristics of patients | PMC10425211 | |||
Summary of adverse events | PMC10425211 | |||
Background | postoperative pulmonary complications | Minimising postoperative pulmonary complications (PPCs) after thoracic surgery is of utmost importance. A major factor contributing to PPCs is the driving pressure, which is determined by the ratio of tidal volume to lung compliance. Inhalation and intravenous administration of penehyclidine can improve lung compliance during intraoperative mechanical ventilation. Therefore, our study aimed to compare the efficacy of inhaled vs. intravenous penehyclidine during one-lung ventilation (OLV) in mitigating driving pressure and mechanical power among patients undergoing thoracic surgery. | PMC10508004 | |
Methods | A double-blind, prospective, randomised study involving 176 patients scheduled for elective thoracic surgery was conducted. These patients were randomly divided into two groups, namely the penehyclidine inhalation group and the intravenous group before their surgery. Driving pressure was assessed at T | PMC10508004 | ||
Results | All 167 participants, 83 from the intravenous group and 84 from the inhalation group, completed the trial. The AUC of driving pressure for the intravenous group was 39.50 ± 9.42, while the inhalation group showed a value of 41.50 ± 8.03 ( | PMC10508004 | ||
Conclusions | Our study found that among patients undergoing thoracoscopic surgery, no significant differences were observed in the driving pressure and mechanical power during OLV between those who received an intravenous injection of penehyclidine and those who inhaled it. Moreover, no significant difference was observed in the incidence of PPCs between the two groups. | PMC10508004 | ||
Keywords | PMC10508004 | |||
Introduction | Postoperative pulmonary complications | Postoperative pulmonary complications (PPCs) are commonly observed during the first postoperative week and have been associated with a prolonged hospital stay [Strategies aimed at decreasing the incidence of PPCs include preoperative functional exercise [Airway driving pressure and mechanical power are two widely used parameters in pulmonary protective ventilation. Airway driving pressure represents the pressure generated by mechanically ventilated patients during inhalation and is expressed as the ratio of tidal volume to lung compliance. It can also be calculated at the bedside by subtracting positive end-expiratory pressure (PEEP) from platform pressure [This clinical trial evaluated the specific roles of driving pressure and mechanical power as mediators in reducing PPCs. A randomised, prospective, and double-blind study was conducted to determine whether inhaled penehyclidine could effectively decrease the incidence of PPCs by reducing individualised drive pressure and mechanical power when compared with intravenous penehyclidine. | PMC10508004 | |
Materials and methods | This prospective trial was conducted at affiliated hospital of Jiaxing University, China, from September 2022 to April 2023. The Institutional Review Board approved this study (2022-LY-164), and it was registered with the Chinese Clinical Trial Registry ( | PMC10508004 | ||
Study population | liver dysfunction, tachyarrhythmia, respiratory tract infections, heart dysfunction, allergies, renal insufficiency, prostatic hypertrophy | MYOCARDIAL INFARCTION, RESPIRATORY TRACT INFECTIONS, NARROW-ANGLE GLAUCOMA, HEART DYSFUNCTION, ALLERGIES, RENAL INSUFFICIENCY, PROSTATIC HYPERTROPHY, HEART | The study included patients aged over 50 years who were undergoing thoracic surgery with OLV lasting expected to more than 45 min. Participants were required to have an American Society of Anaesthesiologists physical status of 1–3 and a postoperative hospital stay of at least 3 days to be eligible for participation. Patients were excluded from the study if they met any of the following criteria: (1) inability to cooperate during inhalation therapy, (2) moderate-to-severe symptomatic prostatic hypertrophy or narrow-angle glaucoma, (3) history of a previous myocardial infarction, severe heart dysfunction (New York Heart Association classification > 3), or tachyarrhythmia within the past 3 months, (4) presence of severe respiratory tract infections with low and thick sputum, (5) severe renal insufficiency requiring renal replacement therapy, (6) severe liver dysfunction (Child–Pugh class C), (7) recent use of anticholinergic drugs on the day before surgery, (8) prohibition from using PEEP, and (9) refused to participate in the trial. Additionally, patients taking other intraoperative anticholinergic drugs, those whose surgeries were cancelled, and patients who experienced serious allergies during surgery were considered as dropout criteria. | PMC10508004 |
Blinding and randomisation | The anaesthesia was administered by an anaesthesiologist who was blinded to the patient grouping, and the postoperative assessment was conducted by a researcher who was also blinded to the patient grouping. All patients received a combination of inhalation and intravenous therapy. In both groups, the study drug, 0.5 mg penehyclidine, was diluted and mixed with 5 mL of normal saline. In group A, patients inhaled penehyclidine with a fraction of inspired oxygen (FiOAn independent investigator generated a computer-based randomisation list. The participants were randomly assigned to the inhalation or intravenous group in a 1:1 ratio using a computer-generated random sequence. The randomisation process involved sealed, sequentially numbered, and opaque envelopes that were kept in the operating room. | PMC10508004 | ||
Procedures | The patient’s information was thoroughly reviewed by the surgeon and nurse before the start of the procedure. Intraoperative monitoring equipment, such as electrocardiogram, oxygen saturation, invasive arterial blood pressure, end-expiratory carbon dioxide, airway pressure, and entropy index, was also meticulously checked to ensure proper connections and functionality. The general anaesthesia approach typically involved a combination of inhalation and intravenous medications, comprising a bolus of propofol (1.5–2.5 mg/kg), rocuronium (0.6–0.8 mg/kg) and sufentanil (0.2–0.5 µg/kg). During the maintenance phase of anaesthesia, sevoflurane, remifentanil, and propofol were used. An appropriate double-lumen tracheal tube was selected based on the patient’s sex (37 for males and 35 for females). The positioning of the double-lumen endotracheal tube and bronchi was determined using fibreoptic bronchoscopy. Additional medications, such as rocuronium, were administered as required during the surgery. The target entropy index was maintained between 40 and 60 during the maintenance phase of general anaesthesia. Anaesthesiologists were given discretion in the use of analgesic pumps or peripheral nerve blocks when possible. Lactated Ringer’s solution was administered as the maintenance fluid at a rate of 3–5 mL/kg/h. Intraoperative vasoactive drugs were administered based on the mean arterial pressure, and routine postoperative antiemetic medications, such as glasnost, were administered.In this study, a standardised ventilation strategy was implemented for each patient. Tidal volume and respiratory rate were set at 6 mL/kg of predicted body weight and 13 breaths per minute, respectively, during OLV. Volume-controlled ventilation was employed with a 30% inspiratory pause and a 1:2 inspiratory to expiratory ratio. The inspired oxygen level was maintained at ≥ 60% and mixed with air. Predicted body weight (PBW) was calculated based on the patient’s sex, with PBW for men calculated as 50 + 0.91 × (height [cm] − 152.4) and PBW for women calculated as 45.5 + 0.91 × (height [cm] − 152.4). Oxygen concentration was increased as required to ensure adequate oxygenation during OLV and maintain a saturation level of at least 95%. After 5 min of OLV, the lowest driving pressure was determined, and PEEP was gradually increased from 0 to 10 cmH | PMC10508004 | ||
Data collection and outcome assessment | For data collection, a standardised form was used, sourced from the clinical charts to obtain baseline characteristics. Baseline data included demographic and morphometric characteristics, preoperative comorbidities, and smoking and alcohol history, along with pulmonary function test results. These pulmonary function test results were categorised based on clinical diagnosis and their reported values: 1) mild (forced expiratory volume in 1 s [FEVIntraoperative data included the types and doses of anaesthetics/medications, anaesthesia duration, fluid balance, mechanical ventilation settings, OLV duration, use of vasoactive drugs (such as ephedrine, phenylephrine, and metaraminol), the surgery type and duration, and the surgical site.The primary outcome of this study was the composite measure of driving pressure, which was assessed at several specific time intervals: T | PMC10508004 | ||
Sample size estimation | During the preliminary study, the driving pressure of 60 patients across T | PMC10508004 | ||
Statistical analysis | Categorical variables are presented as numbers and percentages. Continuous variables are presented as the mean ± standard deviation or median (interquartile). The chi-square test or Fisher’s exact test was used to compare categorical variables and Student’s t-test or Mann–Whitney U test was used for continuous variables, based on the normality of the data. Generalised estimating equations were used for repeated measures. Statistical analyses were performed using SPSS version 25 and GraphPad Prism 9, with a significance level set at 0.05 (two-tailed). | PMC10508004 | ||
Results | From September 2022 to April 2023, 201 patients were initially assessed for eligibility, of which 176 patients were randomised. Nine patients were excluded after randomisation, resulting in 167 patients for per-protocol analysis. The final analysis encompassed 83 patients in the intravenous group and 84 patients in the inhalation group (Fig.
Flow chart for patients undergoing thoracoscopic respiratory mechanical studies
Demographic and baseline data
Intraoperative and postoperative characteristics
| PMC10508004 | ||
Driving pressure | (%)Adverse drug reactions | The AUC for driving pressure did not reveal any significant differences between the inhalation and intravenous groups (41.50 ± 8.03 vs. 39.50 ± 9.42,
Driving pressure and mechanical power during OLV and PPCsIncidence of PPCs within 7 days,n (%)Adverse drug reactions associatedwith penehyclidine, n (%)
Driving pressure. According to generalised estimating equations, no statistically significant difference was observed in the driving pressure between the two groups ( | PMC10508004 | |
Mechanical power | No significant differences were observed between the inhalation and intravenous groups in terms of the AUC of mechanical power (24.00 [20.7–27.9] vs. 24.20 [19.7–27.1];
Mechanical power. According to generalised estimating equations, the mechanical power did not differ significantly in the intergroup comparison ( | PMC10508004 | ||
Secondary outcomes | postoperative pulmonary complications | LUNG | Within 7 days postoperatively, PPCs, categorised according to the Clavien–Dindo classification were observed in 20 of the 84 patients (23.8%) in the inhalation group and 23 of the 83 (27.7%) patients in the intravenous group (
Incidence of postoperative pulmonary complications (PPCs) within 7 days. The incidence of PPCs was 23.8% among patients in the inhalation group compared with 27.7% in the intravenous group within 7 days postoperatively (According to generalised estimating equations, the comparison of lung compliance between the two groups was not significantly different in the intergroup comparison (
Lung compliance. According to generalised estimating equations, lung compliance between the two groups did not differ significantly in the intergroup comparison ( | PMC10508004 |
Safety outcomes | ADVERSE REACTIONS | No significant differences were observed in terms of the adverse reactions associated with penehyclidine, and no serious adverse outcomes were attributed to the study drug (Table | PMC10508004 | |
Discussion | ADVERSE EFFECTS, COMPLICATIONS, POSTOPERATIVE COMPLICATIONS | In this randomised clinical trial involving adults undergoing thoracoscopic surgery, preoperative prophylactic inhalation of penehyclidine did not significantly reduce the driving pressure and mechanical power during OLV compared with intravenous administration. Moreover, there was no observed reduction in PPCs within the first 7 days postoperatively.Preliminary studies have established an association between increased driving pressure and an augmented risk of complications and mortality [Previous retrospective studies have drawn attention to a concerning connection between the excessive application of mechanical power during surgery and an increased risk of postoperative complications [Penehyclidine, a novel anticholinergic drug, specifically targets M1 and M3 receptors and achieves peak plasma concentration around 0.56 h after administration [Nebulised drug inhalation delivers the drug directly to the airway, resulting in a higher local concentration and faster onset of action, with fewer systemic adverse effects. However, the absence of a significant difference between the inhaled and intravenous groups in our study might be attributed to the inhalation technique employed and the drug’s blood concentration. Further research should focus on determining the optimal dosage and inhalation method for nebulised drugs.There are several limitations to this study. First, the absence of a placebo-controlled trial to demonstrate the effectiveness of penehyclidine on driving pressure and mechanical power is notable. This limitation stems from the requirement of routine anticholinergic administration during thoracic surgery to manage secretions. Second, our inability to determine the blood concentration and peak time after penehyclidine inhalation posed challenges in aligning the duration of action with intravenous administration. Third, this study concentrated on determining the driving pressure and mechanical power during OLV, however, it did not factor in the respiratory mechanics during two-lung ventilation, which could influence the reliability of the research results. Fourth, wedge resection has been found to have a low rate of PPCs in thoracic surgery [ | PMC10508004 | |
Acknowledgements | We are grateful to the cardiothoracic surgeons of the Jiaxing University affiliated hospital for their assistance. Additionally, we would like to thank Zhiyun for their significant input in revising the wording of this paper. | PMC10508004 | ||
Authors' contributions | Ming-zi An and Qing-he Zhou were major contributors to this study. Te-sheng Gao, Qing-he Zhou and Ming-zi An contributed to the study conception and design. Data were collected by Cheng-yun Xu, Yue-ru Hou and Zhen-ping Li. The data analysis was performed by Ming-zi An and Qing-he Zhou. The first draft of the manuscript was written by Ming-zi An. All authors read and approved the final version of the manuscript. | PMC10508004 | ||
Funding | This study was supported by Zhejiang medical and health science and technology plan project (2023KY341), Jiaxing Key Discipiline of Medcine --Anesthesiology (2023-ZC-001), the Key Discipline Established with Zhejiang Provincial Traditional Chinese Medical Innovation Team (No. 2022-19) and Zhejiang Provincial Key Clinical Specialty—Anesthesiology (2022-01). | PMC10508004 | ||
Availability of data and materials | All the data and material generated during the current study are available from the corresponding author upon reasonable request (zqh10980@zjxu.edu.cn). | PMC10508004 | ||
Declarations | PMC10508004 | |||
Ethics approval and consent to participate | This trial was approved by the ethics committee of the Affiliated Hospital of Jiaxing University, China, on September 06, 2022 (2022-LY-164) before experiment was started and that has been conducted in accordance with the principles set forth in the Helsinki Declaration. Written informed consent was obtained from all participants or their guardians. | PMC10508004 | ||
Consent for publication | Not applicable. | PMC10508004 | ||
Competing interests | The authors declare no competing interests. | PMC10508004 | ||
References | PMC10508004 | |||
Background | sleep disorders, insomnia, sleep disorder | CHRONIC INSOMNIA | Shift workers are at high risk of developing sleep disorders such as shift worker sleep disorder or chronic insomnia. Cognitive behavioral therapy (CBT) is the first-line treatment for insomnia, and emerging evidence shows that internet-based CBT is highly effective with additional features such as continuous tracking and personalization. However, there are limited studies on internet-based CBT for shift workers with sleep disorders. | PMC10481224 |
Objective | sleep disorders | This study aimed to evaluate the impact of a 4-week, physician-assisted, internet-delivered CBT program incorporating machine learning–based well-being prediction on the sleep duration of shift workers at high risk of sleep disorders. We evaluated these outcomes using an internet-delivered CBT app and fitness trackers in the intensive care unit. | PMC10481224 | |
Methods | SYNDROME | A convenience sample of 61 shift workers (mean age 32.9, SD 8.3 years) from the intensive care unit or emergency department participated in the study. Eligible participants were on a 3-shift schedule and had a Pittsburgh Sleep Quality Index score ≥5. The study comprised a 1-week baseline period, followed by a 4-week intervention period. Before the study, the participants completed questionnaires regarding the subjective evaluation of sleep, burnout syndrome, and mental health. Participants were asked to wear a commercial fitness tracker to track their daily activities, heart rate, and sleep for 5 weeks. The internet-delivered CBT program included | PMC10481224 | |
Results | In the fourth week of intervention, the mean daily sleep duration for 7 days (6.06, SD 1.30 hours) showed a statistically significant increase compared with the baseline (5.54, SD 1.36 hours; | PMC10481224 | ||
Conclusions | sleep disorders | The physician-assisted internet-delivered CBT program targeting shift workers with a high risk of sleep disorders showed a statistically significant increase in sleep duration as measured by wearable sensors along with subjective sleep quality. This study shows that sleep improvement programs using an app and wearable sensors are feasible and may play an important role in preventing shift work–related sleep disorders. | PMC10481224 | |
International Registered Report Identifier (IRRID) | RR2-10.2196/24799. | PMC10481224 | ||
Introduction | PMC10481224 | |||
Interventions for Shift Work–Related Sleep Disorder | insomnia, SWSD | Shift work is common among the working population, with approximately 20% of individuals engaged in shift work [Cognitive behavioral therapy (CBT) is a treatment aimed at restructuring undesired thinking and modifying behavioral patterns through self-reflection and interactions with physicians. There are 4 fundamental psychotherapy techniques used in CBT: cognitive restructuring, behavioral activation, exposure, and problem-solving [Several studies have adapted CBT for insomnia in shift workers. Some components of CBT for insomnia, such as sleep hygiene promotion and relaxation techniques, are considered to be equally effective for SWSD. In addition, similar to insomnia, sleep diaries or actigraphs are recommended to assess sleep disturbances and to evaluate the effects of treatment. However, the literature suggests that simply applying CBT for insomnia in shift workers may not result in an improvement in insomnia symptoms. In a study, CBT for insomnia was effective when shift workers were excluded from the analysis [ | PMC10481224 | |
Shift Workers’ Well-Being and Well-Being Prediction | Several studies have shown a correlation between poor sleep patterns resulting from shift work and an increased risk of burnout among various professional groups, including police officers [The second aim was to provide “well-being prediction” feedback to the participants. Previous studies have shown that self-monitoring prompts users to self-reflect and improve their behaviors, such as eating and exercise. Reflection is an essential activity in personal informatics apps that enable users to generate insight for self-improvement and make behavioral or mental changes [ | PMC10481224 | ||
Objectives | sleep disorders | This study aimed to evaluate the effect of a physician-assisted, internet-delivered CBT intervention with machine learning–based well-being prediction on sleep duration and well-being of shift workers at high risk of sleep disorders. The study followed a single-arm prospective design, with a baseline period of 1 week, followed by a 4-week intervention period. The participants were shift workers from the ICUs of 2 hospitals. Sleep duration and other relevant outcomes were assessed using a combination of an internet-delivered CBT app and a fitness tracker. | PMC10481224 | |
Methods | PMC10481224 | |||
Study Design and Settings | sleep disorders | This prospective interventional study aimed to evaluate the effect of internet-delivered CBT on shift workers with a high risk of sleep disorders. This study involved shift workers, including physicians and nurses, employed in 2 ICUs in Japan. Participants were instructed to wear a wrist-worn fitness tracker 24 hours a day and answer daily questionnaires about their well-being and activities. Internet-delivered CBT was provided through an app installed on the participants’ phones. We compared the total sleep duration, subjective well-being, and other variables in the baseline and intervention periods.The participants were recruited using flyers and email, both including the same content that stated the aim of the research project, the participant’s eligibility requirements, intervention methods, and participant’s rights. The emails were distributed by the head of the department to all employees. The flyers were handed out at staff meetings. After the flyers and emails were distributed, a research assistant asked all eligible employees about their intention to participate. After inclusion, the participants were completely anonymous to the study team and sleep physicians who reviewed the participant’s data and provided sleep advice (see details in the | PMC10481224 | |
Inclusion and Exclusion Criteria | narcolepsy, psychiatric, sleep disorders | DISORDERS, SLEEP APNEA, NARCOLEPSY, RESTLESS LEG SYNDROME | Inclusion criteria were as follows: shift workers engaged in emergency and intensive care areas, working on a 3-shift schedule with 8-hour shifts, and a Pittsburgh Sleep Quality Index (PSQI) score ≥5. Exclusion criteria were as follows: diagnosis of sleep disorders such as sleep apnea, restless leg syndrome, and narcolepsy; previous history of psychiatric disorders; and pregnancy. Participants with these diagnoses were excluded from the study so that the intervention or sleep advice would not interfere with the present medical treatment. The participants were assessed for eligibility according to self-reported past medical history or pregnancy and the PSQI test. The participants were asked if any of the exclusion criteria applied to them. | PMC10481224 |
Study Measures and Outcomes | PMC10481224 | |||
Objective and Subjective Sleep Measurements | The primary outcome of this study was to evaluate the effect of the intervention on total sleep time. In this study, we used a consumer fitness tracker called Fitbit Charge 3 (Fitbit). It is widely used in sleep research under normal living conditions because of its easy obtainability, cost efficiency, and comparability with polysomnography [ | PMC10481224 | ||
Subjective Well-Being and Mental Health State | calmness, Anxiety, PVT: psychomotor vigilance | SECONDARY | As a secondary outcome, we evaluated the effect of the intervention on subjective well-being. Participants scored their subjective well-being using 5 categories: alertness, happiness, energy, physical health, and calmness. Participants were asked to rate their subjective well-being on a scale of 0 to 100 as part of their morning and evening daily surveys. Other questions in the daily survey included activities and habits (eg, alcohol and caffeine intake). The 5 categories of well-being and other surveys were used in a prior study of well-being prediction [We also compared several validated questionnaires on mental health and burnout symptoms before and after the intervention (Intervention and measurement schedules. Well-being prediction and the activity and sleep chart was available to the participants every day, whereas sleep advice was provided 3 to 4 times a week. The participants answered the pre and postintervention questionnaires and daily morning and evening surveys. GHQ: General Health Questionnaire; JBS: Japan Burnout Score; PSQI: Pittsburgh Sleep Quality Index; PVT: psychomotor vigilance test; STAI: State-Trait Anxiety Inventory. | PMC10481224 |
Sample Size and Power Calculation | Before this study, we collected data from 16 shift workers in a pilot study. The mean sleep duration was 334.68 (SD 135.1) minutes. On the basis of the pilot study data with a small sample, the mean sleep duration at week 4 of the intervention was assumed to be 30 minutes longer, with no change in SD. Assuming a 2-sided level of significance of 5%, power of 80%, and correlation coefficient of 0.8, using the SAS system (SAS Institute Inc), 66 participants were required for a significant difference to be found in the 2-tailed paired | PMC10481224 | ||
Intervention | sleep disorders | The smartphone app for the intervention was developed and made available as a Progressive Web Application so that it could be used on an iOS or Android device (Well-being prediction is an essential component of an app. On the basis of earlier studies on machine learning and subjective well-being [The second essential component is personalized sleep advice from physicians. Participants received personalized sleep advice from 2 board-certified psychiatrists specializing in sleep disorders and CBT 3-4 times a week. The advice was suggested after the psychiatrists reviewed the fitness tracker data and surveys, without seeing the well-being prediction results. This ensured that sleep advice was solely based on the physician’s clinical judgment. Physicians chose 3 to 5 messages among 23 fixed-format sleep advice messages (eg, “Avoid alcohol before you go to sleep” and “Try to wake up at a consistent time.”; On the “activity and sleep chart” tab, the participants were readily able to see how much activity and sleep they had in 24 hours for the past 7 days, along with their shift schedule. These data were retrieved every hour from the Fitbit server using its web application programming interface. The intervention has been described in detail in a previous study protocol [The user interface of the app, translated from Japanese to English. Left: Awake times are displayed as red bars, where higher activity levels (higher number of steps/min) are shown in deeper shades of red. Sleep times are displayed as blue bars, where deeper sleep stages are shown in deeper shades of blue. Right: The happiness score is illustrated by a graphic that resembles a weather forecast: cloudy for scores 0 to 50, cloudy and partly sunny for scores 60 to 80, and sunny for scores 90 to 100. | PMC10481224 | |
Statistical Analyses | Statistical analyses were performed using SPSS Statistics for Macintosh (version 25.0; IBM Corp). The baseline characteristics of the study population were expressed as mean and SD for quantitative variables. For the primary outcome of this study, the mean sleep duration at week 4 of the intervention and the means and SDs of sleep duration were calculated at both the baseline data collection period and at week 4 of the intervention period. For the primary end point, a 2-sided paired | PMC10481224 | ||
Ethics Approval | MAY | This study was approved by the Clinical Research Ethics Review Committee of Mie University Hospital, Tsu, Japan (H2020-083). This study was approved by the ethics committee of the Suzuka General Hospital (review number 254). All procedures were performed in accordance with the ethical standards of the Institutional Research Committee and 2013 Declaration of Helsinki. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry on May 1, 2020 (ID: UMIN000040547). | PMC10481224 | |
Results | PMC10481224 | |||
Changes in Well-Being and Mental Health | There was no significant improvement in all 5 well-being scores (alertness, happiness, energy, health, and relaxation; all | PMC10481224 | ||
Postanalysis of Well-Being Prediction | After the study, the performance of the prediction model was evaluated. Postanalysis showed that the macroaveraged | PMC10481224 | ||
Discussion | PMC10481224 | |||
Principal Findings | sleep disorders, insomnia | DISORDERS | The main result of this study shows that physician-assisted internet-delivered CBT program in shift workers with a high risk of sleep disorders increased total sleep time, as measured using commercially available fitness trackers. After a 4-week intervention period, the mean daily sleep duration for 7 days (6.06 hours) showed a statistically significant increase compared with the baseline (5.54 hours; In a systematic review of interventions for shift workers, it was found that studies that improved sleep reported increases in sleep duration ranging from 0.34 to 0.99 hours in randomized controlled trials and from 0.02 hours to 1.15 hours for nonrandomized controlled trials [Contrary to expectations, this study did not find an improvement in subjective well-being except for “energy” in the morning. In addition, we did not find any improvement in burnout levels. However, the feature importance analysis of well-being prediction showed that sleep duration, steps, and type of shift were factors with high relevance. A possible explanation for these contradicting results might be that sleep is simply one component of well-being or that sleep deprivation may be the result of burnout. In a study on physicians, career satisfaction, work hours, and family support were among the most relevant factors affecting well-being [Furthermore, one of the significant features of the proposed internet-delivered CBT program is that it combines the benefits of physician assistance with the positive aspects of self-help apps, such as promoting self-reflection and facilitating behavioral change. Several studies have demonstrated that internet-delivered CBT with the involvement of physicians or therapists is highly effective. A systematic review comparing internet-delivered therapy with face-to-face therapy found no significant differences in outcomes such as sleep efficiency, total sleep time, and insomnia severity. In 10 out of 15 trials included in the review, physician or therapist involvement, including weekly feedback, was integrated into the internet-delivered therapy [Another feature of this 4-week intervention is that the target was shift workers with sleep disorders ranging from mild to severe symptoms who were not previously diagnosed with sleep disorders or other mental health disorders. Although shift work is associated with several health issues, shift workers are essential to the health care system. Although in severe cases, adjustment of shift schedules may be the best solution, this is not usually feasible for shift workers with mild symptoms. From an occupational health perspective, interventions to leverage the health of the overall working population are needed other than providing special treatment or absence for those that exceed preventive measures. Internet-delivered intervention allows users to engage in the program on their own time, allowing flexibility and instant support, and can be tailored to the user’s needs [ | PMC10481224 |
Limitations | anxiety | Our study has a few important limitations. First, this study does not provide any conclusion to the participants’ motivation for attribution and continuation, as the research incentives were financial rewards. We acknowledge that motivation and participation are crucial factors that affect the outcomes of internet-based interventions. Nevertheless, as the incentive was merely for participation in the study and not based on any accomplishment or goals, the effect did not directly interfere with the outcome. Second, the study did not include a control group owing to the limited number of participants. We do not know whether monitoring with a consumer-targeted health tracker alone would improve the sleep-related outcomes. However, research implies that although sleep tracking devices can help users better understand and improve their overall sleep habits, excessive focus on sleep feedback provided by only the tracking devices may derail users from focusing on modifiable behaviors and sleep hygiene or may exacerbate anxiety about sleep [ | PMC10481224 | |
Conclusions | sleep disorders, Epilepsy | EPILEPSY | Physician-assisted, internet-delivered CBT for shift workers with a high risk of sleep disorders showed significant improvement in sleep duration, as measured by wearable sensors, and subjective sleep quality. This study implies that sleep improvement programs using an app and wearable sensors are feasible and may play an important role in preventing shift work–related sleep disorders. However, no relationship was observed between sleep changes and subjective well-being. Further studies should focus on the causal relationship between daily well-being and sleep disorders related to shift work.This research was funded by the Japan Agency for Medical Research and Development (#19217687) and the National Science Foundation (#1840167). This manuscript was edited for English language by Editage.Conflicts of Interest: AS has received travel reimbursement or honorarium payments from Leuven Mindgate, American Epilepsy Society, IEEE, and Apple. AS has also received research support from Microsoft, Sony Corporation, NEC Corporation, Pola Chemicals, and Meta and consulting fees from Gideon Health and Suntory Global Innovation Center.Description of the fixed-format sleep advice.Results of ANOVA showing the effect of sex and age group on each subjective well-being score.Heat map of the measured variables.Change in the mean sleep duration before and after the intervention in female and male shift workers. | PMC10481224 |
Abbreviations | Anxiety | DISORDER | cognitive behavioral therapyGeneral Health Questionnaireintensive care unitPittsburgh Sleep Quality Indexpsychomotor vigilance testState-Trait Anxiety Inventoryshift worker sleep disorder | PMC10481224 |
MATERIALS AND METHODS | PMC10071780 | |||
Population | RECURRENCE | This study was a prospective, open-label, randomized, 2-armed crossover study conducted in 6 study centers in France. Men who were at least 18 y old, who were diagnosed with PCa, and who had prior definitive therapy were considered for enrollment. Eligible patients presented with suspected PCa recurrence, defined as 3 consecutive PSA increases or a PSA rise of greater than or equal to 2.0 ng/mL above the nadir after radiotherapy (external-beam radiation therapy or brachytherapy) or cryotherapy or a PSA rise of greater than or equal to 0.2 ng/mL after prostatectomy. The main exclusion criteria were participation in another therapeutic clinical trial within 5 d of enrollment in the present study and a life expectancy of less than 6 mo.The study protocol was approved by a national ethics committee certified by the French Ministry of Health (Institutional Review Board: IORG0009855). All patients gave written informed consent before randomization. | PMC10071780 | |
Intervention | All men underwent both | PMC10071780 | ||
Image Reading and Standard of Truth | RECURRENCE | PET images were read on-site on the day of acquisition by investigators who were not masked regarding clinical data and were transferred to a core imaging laboratory where they were evaluated by 3 independent masked readers (supplemental materials). The composite standard of truth (recurrence, no recurrence, or undetermined) at the time of imaging was determined by an independent expert panel that considered all available clinical patient data from before inclusion to the end of the follow-up period, excluding all information from PET/CT (supplemental materials). The expert panel consisted of a urologist, a radiologist, and a nuclear physician; they reached their conclusions by consensus. | PMC10071780 | |
Outcomes | The primary objective was to compare Secondary objectives were to compare the correct detection rates of the clinical investigators; to assess the correct detection rates of both radiotracers for PCa lesions in a region-based analysis; to report the impact on diagnostic thinking (impact of PET/CT result on posttest vs. pretest probability of a correct diagnosis), therapeutic decision making (impact on the comprehensive process by which physicians make decisions about the PCa response), and adequacy of management changes by the Investigators at 3 time points (before PET, immediately after both PET studies, and at the end of follow-up) and by the expert panel (only at the end of follow-up), using 3 dedicated forms (supplemental materials); to compare the masked intra- and interreader agreements; and to assess the safety profile of | PMC10071780 | ||
Statistical Analysis | Analysis was performed using SAS 9.4 or higher (SAS Institute), detailed in the supplemental materials. A | PMC10071780 | ||
RESULTS | PMC10071780 | |||
Population | From March 5, 2019, to October 8, 2020, 200 patients consented to this study; 195 were randomized, and 189 completed all follow-up assessments (Trial chart.Patient Characteristics (Intention-to-Treat Population)Values in parentheses are ranges.Reported as numbers of patients, with percentages in parentheses.Reported as medians, with interquartile ranges in parentheses.ISUP = International Society of Urological Pathology.The median follow-up period for the ITT population was 8.3 mo (range, 2.9–16.1 mo), as its duration was extended because of the COVID-19 pandemic. | PMC10071780 | ||
Primary Objective | RECURRENCE, METASTASES, POSITIVE | Per-patient and per-region PET findings are detailed in the supplemental materials. At the patient level, the masked readers found evidence for PCa recurrence in 145–162 patients (76.3%–85.3%) with The overall proportion of patients with correct detection rates for PCa lesions with Patient-Level Overall Proportion of Patients With Correct Rate of Detection of Recurrent PCa According to Standard of Truth and Positive Predictive Value (ITT Population) (Values in parentheses are 95% CIs.For both study drugs, the correct detection rate for PCa recurrence was higher for patients with higher PSA levels. For all examined PSA-level subgroups, the correct detection rate was statistically higher for Patient-Level Proportion of Patients With Correct Rate of Detection of PCa Lesions by PSA Level at Baseline (ITT Population) (Values in parentheses are 95% CIs.SOT = standard of truth.Masked intra- and interreader agreements for the detection of metastases (patient level) ranged from 0.24 to 0.73 and from 0.30 to 0.36 for | PMC10071780 | |
Secondary Objectives | PMC10071780 | |||
Comparison of Patient-Based Correct Detection Rates According to Investigator Findings | On the basis of the clinical investigators’ overall findings, the correct detection rates were 0.80 (95% CI, 0.74–0.86) for | PMC10071780 | ||
Comparison of Region-Based Correct Detection Rates According to Masked Readers’ Findings | In the 72 patients for whom 1 or more regions could be assessed by the expert panel, there were 78 regions with confirmed PCa lesions. The most common sites for PCa lesions were the pelvis (59 patients) and the spine (6 patients) (supplemental materials). In the patients considered to have a positive PET result, more suggestive lesions were detected with Overall composite region-level sensitivities were 0.77 (95% CI, 0.69–0.84) for | PMC10071780 | ||
Impact on Diagnostic Thinking, Therapeutic Decision Making, and Adequacy of Therapy Changes | The investigator assessments of the changes in diagnostic thinking after both PET/CT examinations and at the end of follow-up are summarized in Change in Diagnostic Thinking After Both PET/CT Scans (ITT Population) (Data are reported as numbers of patients, with percentages in parentheses.Change in Diagnostic Thinking After Both PET Scans and Influence at End of Follow-up (ITT Population) (Data are reported as numbers of patients, with percentages in parentheses.In 122 patients, PET/CT led to a more accurate diagnosis that benefited them. In 11 patients, PET/CT was not to the benefit of the patient, and in 45 patients, PET/CT did not exert a positive or negative influence. In the 122 patients with a more accurate diagnosis after PET/CT that benefited them, | PMC10071780 | ||
Safety Profile of | toothache, diarrhea | ADVERSE EVENTS, EVENTS, ADVERSE EVENT, ARTERIAL HYPERTENSION | There were no serious adverse events. No patient discontinued study participation because of an adverse event. Four patients had 4 events (toothache, diarrhea, chest discomfort, and arterial hypertension) after the administration of | PMC10071780 |
DISCUSSION | prostate | RECURRENCE, PROSTATE | To our knowledge, the present study is the first multicenter, crossover randomized study to compare The investigator assessments after PET/CT and at the end of follow-up demonstrated the superiority of The strengths of our study are its prospective, multicenter, randomized crossover design. Limitations include the lack of histopathology for most lesions. Because obtaining histopathology is often ethically questionable or medically impractical, our standard of truth was a composite based on biopsy, response to local therapy, imaging, and changes in serum PSA levels during 6 mo of follow-up, as established by an independent panel of experts. The use of the independent panel removed potential bias in determining “truth” while modeling what is done in “real-life” practice.In this work, we found that 62-y-old patient with history of PCa (International Society of Urological Pathology grade 3; PSA level of 5.7 ng/mL), initially treated with prostatectomy (pT3N0R0), prostate bed radiation therapy, and 6 mo of androgen deprivation therapy (ADT), presenting with PSA recurrence (0.72 ng/mL). | PMC10071780 |
CONCLUSION | This prospective, multicenter, open-label, crossover randomized study demonstrated that | PMC10071780 | ||
DISCLOSURE | This study was funded and supported by ABX Advanced Biochemical Compounds, Radeberg, Germany. Ines Rudolph and Alexander Hoepping work for ABX Advanced Biochemical Compounds. Charles Merlin has received personal fees and nonfinancial support from Curium Pharma and Novartis. Mathieu Gauthé has received personal fees and nonfinancial support from Astellas, Curium Pharma, and Novartis. The manuscript was edited for English language by Dr. Jay R Wiggins, PhD, and Dr. Kelsey L. Pomykala, MD, supported by ABX Advanced Biochemical Compounds. The ABX-CT-301 | PMC10071780 | ||
ACKNOWLEDGMENTS | P. | We thank the following institutions and people for participating in this study: Hôpital Tenon—F. Montravers, C. Aveline, J.N. Talbot, T. Rusu, B. Mugnier, and N. Cailleux; HEGP—B. Clara, M. Bernardini, C. Smadja, H. Slimani, B. Truffault, and M. Homo Seban; CHRU Nancy—G. Karcher, P. Eschwege, M. Claudin, and D. Peiffert; Centre Léon Bérard—P. Pommier, C. Carrie, C. Laude, A. Serre, J.N. Badel, T. Mognetti, A. Lauret, and O. Osman; HCL—I. Morelec, A. Dhomps, J. Tordo, P. Got, C. Darcissac, F. Hallouard, P. Bonazza, and H. Belhouli; and Centre Jean Perrin—C. Bouvet, B. Barres, E. Villeneuve, C. Valla, M. Tempier, G. Loos, M. Chanchou, A. Kelly, J. Amat, P. Bouyon, L. Viala, F. Luzuy, J. Miroir, and F. Cachin. | PMC10071780 | |
REFERENCES | PMC10071780 | |||
Background | DRY EYE, DISORDER | Lifestyle modification is a newly recommended complementary treatment for dry eye (DE) disorder. | PMC10692261 | |
Objective | hypertensive | OBESE | To investigate the effect of a 6-month high-intensity interval aerobic exercise (HIIAE) (conducted 30 min, 3 times weekly) alone or combined with a caloric-restriction approach, the Mediterranean diet (MD), on DE parameters in obese hypertensive elderly. | PMC10692261 |
The design, settings, participants, and intervention | hypertensive | OBESE, RECRUITMENT | This is a randomized controlled trial included sixty obese hypertensive elderly with DE based on university-based hospital recruitment. Elderly were randomly assigned to the experimental group ( | PMC10692261 |
Results | Significant improvements in anthropometry, blood pressure, and DE parameters were higher in the experimental group than in the control group. | PMC10692261 | ||
Conclusion | DE disorder, hypertensive | OBESE | Aging-related DE symptoms and signs can be prevented and/or treated with HIIAE alone or combined with MD in obese hypertensive elderly with DE disorder.
| PMC10692261 |
Keywords | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC10692261 | ||
Introduction | obesity, ocular pain, redness, impairments of the lacrimal gland, itching, fatigue, inflammation, dry eye, Tear deficiency, atrophy, tear film disorder, diabetes | OBESITY, METAPLASIA, INFLAMMATION, DISEASE, ASSOCIATED DISEASE, DRY EYE, ATROPHY, METABOLIC SYNDROME, HYPERTENSION, COMPLICATIONS, DIABETES | Tear deficiency or excessive evaporation is the main descriptive definition of the tear film disorder, dry eye (DE). DE can damage the interpalpebral ocular surface with subsequent symptoms of ocular discomfort [The symptomatic discomfort expresses itself in DE as ocular pain, itching, scleral redness, light sensitivity, fatigue or strain, heavy or foreign body sensation, and discharge [The global percentage of DE prevalence ranges from 5 to 87.5 [Physiological and structural ocular changes that occur with biological aging may explain the mechanism of DE in the elderly. Decreased tear secretion/volume, increased tear evaporation, apparent impairments of the lacrimal gland (histological, functional, and structural impairments), atrophy of the meibomian gland (this gland secretes the tear-containing lipid layer), and metaplasia of ocular orifices are local ocular changes predispose DE with aging. Low-grade chronic local and systemic inflammation is another apparent sign of DE in the elderly due to the aging of their immune system [As life expectancy increases, the elderly tend to have a sedentary lifestyle. This lifestyle is the cause of elderly’s obesity and its associated diseases and/or complications including hypertension, diabetes, metabolic syndrome, and the highly prevalent DE [Nowadays, the available medical treatments for DE are frustrating for sufferers and ophthalmologists [Considering DE a lifestyle disease, the application of caloric restrictive and exercise approaches is an advisable lifestyle for DE patients [ | PMC10692261 |
Materials and methods | PMC10692261 | |||
Study design | The design was as follows: single-blinded evaluation of DE parameters (conducted by an ophthalmologist who did not share in MD or HIIAE and both interventions were masked from him), the prospective registration of this lifestyle-modification study on clinicaltrials.gov (NCT05248698), and the randomized controlled followed designs. | PMC10692261 | ||
Setting | RECRUITMENT | DE patients’ recruitment was managed from the ophthalmology outpatient clinic of Cairo University hospitals. The exercise sessions were supervised by the two physiotherapy authors of this study in a physical therapy center (a private center located in Cairo) from 5th January to 30th December 2022. | PMC10692261 |
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