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Subject terms | congenital heart disease, CHD | We aimed to explore the effects of perioperative exercise on cardiorespiratory endurance in children with congenital heart disease (CHD) in plateau areas after surgical repair. Fifty children with CHD in the plateau admitted to our hospital were randomly divided into the exercise and control groups. The exercise group received a perioperative exercise intervention beginning within 24 h postoperatively, while the control group received routine nursing and treatment alone. To assess the 6 min walk distance (6MWD) at baseline and at end of intervention, children participated in a 6-min walk test before cardiac repair and at 1 week after general ward transfer. A subset of children in the study underwent the cardiopulmonary exercise test pre-operatively. The 6MWD of children with CHD at baseline was positively correlated with the peak oxygen uptake pre-operatively. No significant difference was reported in the preoperative baseline data of both groups. The 6MWD of the exercise group was significantly higher than that of the control group. Early exercise therapy after cardiac repair could significantly improve the cardiorespiratory endurance and exercise capacity of children with CHD in plateau areas. | PMC10593799 | |
Introduction | Congenital heart disease, congenital disease, CHD | CONGENITAL DISEASE, DISEASES | Congenital heart disease (CHD) is the most common congenital disease in newborns; it is caused by abnormal development of the heart and/or large blood vessels in the fetus and includes heart wall, valve, and vascular malformationsAn active lifestyle is critical to the long-term health of patients with CHD. The current treatment of such patients no longer aims solely at short-term survival, however, the aim is long-term physical health, development, and well-beingThe Cochrane studyThe cardiopulmonary exercise test (CPET) has been increasingly used to preoperatively evaluate various diseases and treatment effects and formulate rehabilitation prescriptions, as it can evaluate exercise physiology, reflect the multisystem functions of the body in real-time during exercise, and objectively evaluate the patients’ cardiovascular functionIn cases where CPET is not feasible, such as inpatient settings or immediate postoperative period, the 6‑min walk test (6-MWT) is an alternative measure of cardiorespiratory endurance that has also been applied as the basis of function-based prognostic assessmentTherefore, this study used device-based objective assessments and interventions to explore the characteristics of growth, development, and cardiorespiratory endurance of children with CHD in plateau areas. It evaluated the effect of an early exercise intervention after cardiac repair on the exercise capacity and cardiorespiratory endurance of these children. Ultimately, our aims were achieved. | PMC10593799 |
Methods | PMC10593799 | |||
Patient information | The study protocol was approved by the ethics committee of Zhengzhou Cardiovascular Hospital, affiliated to Southern Medical University (2020-10-002-F02). Patients in plateau areas who were admitted to the Cardiovascular Surgery Department of Zhengzhou Cardiovascular Hospital] between January 2020 and July 2022 were included. Parents or guardians of all of the patients provided signed informed consent prior to the study. The procedures followed were in accordance with the ethical standards of the relevant institutional committee on human experimentation and with the 1975 Helsinki Declaration, as revised in 2000. | PMC10593799 | ||
Inclusion criteria | CHD | The inclusion criteria were CHD diagnosed using cardiac color Doppler ultrasound that required surgical repair after evaluation, the ability to independently complete the 6-MWT and exercise training procedure, aged less than 18 years, and signed informed consent by the parent or guardian. | PMC10593799 | |
Exclusion criteria | emphysema | RESPIRATORY INSUFFICIENCY, HYPERSENSITIVITY, EMPHYSEMA | The exclusion criteria were unstable vital signs, the inability to perform exercise due to muscle and joint problems, severe instability of the airways (patients with severe emphysema), bronchial non-specifically marked hypersensitivity, and severe gas exchange impairment (total or partial respiratory insufficiency). | PMC10593799 |
Withdrawal criteria | POSTOPERATIVE COMPLICATIONS | Patients could withdraw from the study voluntarily or if they were unable to complete the study procedures due to serious postoperative complications. | PMC10593799 | |
Collection of basic clinical data | After admission, age, sex, height, and weight of each enrolled patient were collected. Body mass index (BMI) was calculated, and the left ventricular ejection fraction (LVEF) was assessed using echocardiography. | PMC10593799 | ||
Exercise ability assessment | PMC10593799 | |||
Preparation of the patient | AIDS | (1) The patient should wear comfortable clothing as well as appropriate shoes for exercise. (2) Patients should use their usual walking aids during the test (cane, walker, etc.) (3) The patient’s usual medical regimen should be continued. (4) A light meal is acceptable before early morning or early afternoon tests. (5) Patients should not have exercised vigorously within 2 h of the test’s start. | PMC10593799 | |
Preparation of the test | (1) Make sure the ambient temperature was kept at 20–25 °C with proper ventilation. (2) Repeat testing was performed at approximately the same time each day by the same professionally trained technician who was unaware of the groupings. (3) A “warm-up” period before the test should not be performed. (4) The serial number, name, age, height, and sex were accurately registered. (5) The patient should sit at rest in a chair, located near the starting position, for at least 10 min before the test starts. During this time, contraindications were assessed, pulse and blood pressure were measured, and clothing and shoes were confirmed to be appropriate. | PMC10593799 | ||
Performing the cardiopulmonary exercise test | dyspnea | BLOOD | An incremental, symptom-limited CPET was performed on a cycle ergometer (Jaeger, German model: MasterScreen CPX)) with continuous measurements of oxygen consumption, carbon dioxide production, minute ventilation, heart rate, 12-lead electrocardiography, and oxygen saturation measured by pulse oximetry. Average resting indices were measured for 30 s prior to initiation of exercise. Blood pressure was calculated at rest and then every 2 min. Gas exchange data were measured breath-by-breath during the four stages of exercise at a pedaling rate of 60 revolutions per minute (rpm): (1) 3 min of rest, (2) 3 min of unloaded exercise, (3) a maximum incremental ramp (15 or 25 Watt/min), and (4) recovery with 5 min of unloaded cycling. The Borg 6–20 Rating of Perceived Exertion (RPE) scale was used to assess the perceived exertion and dyspnea.The main exercise parameters were obtained at peak exercise points, corresponding to the highest work rate achieved and maintained for 30 s, consist of (a) load at peak, (b) peak oxygen consumption (VO | PMC10593799 |
Performing the 6-MWT | THORACIC | The 6-MWT was performed on flat ground in a hospital room. In accordance with the guidelines of the American Society of Thoracic Surgery, the total length was 30 meters (m). Marks were made at every 3 m, and there were signs at the turn-back point. Participants were instructed to walk with the following information:(1) Objective of the test: to walk as far as possible for 6 min. Running or jogging is not allowed. (2) Rest periods during the test: as 6 min is a long time to walk, the patient will be exerting him/herself. If he/she gets out of breath or becomes exhausted, they are permitted to slow down, stop, and rest as necessary. He/she may lean against the wall while resting, but he/she must resume walking as soon as he/she is able. (3) Route to walk (with a practical example by the physician or other trained personnel): position the patient at the starting line and stand near the starting line during the test. The physician/technician cannot walk with the patient. Invite the patient to start walking as soon as he/she is ready. | PMC10593799 | |
Exercise training procedure | All children with CHD were postoperatively admitted to the intensive care unit. Within 24 h of being transferred from the intensive care unit to the general ward, the exercise group received exercise therapy based on the routine nursing treatment of the control group. The bedside power bicycle 30-min intervention program, which included 5 min of warm-up, 20 min of exercise therapy, and 5 min of recovery, was added to their treatment. The target heart rate during exercise was 20–30% higher than the basal heart rate (once per day). Breath-holding was avoided during the intervention process, and effective diaphragmatic breathing was incorporated. Cardiovascular specialists and rehabilitation therapists monitored and recorded the exercise process to ensure the safety of the participants. | PMC10593799 | ||
Statistical analysis | The primary hypothesis of the current study was that children who received a perioperative exercise intervention beginning within 24 h postoperatively would show significantly higher 6MWD than those who received routine nursing and treatment. According to our pre-experiment, based on a two-sided t-test with an All statistical analyses were performed using SPSS software version 22.0 (IBM Corp., Armonk, NY, USA). Enumeration data are expressed as the number of cases and rates (%), and comparisons between groups of enumeration data were performed using the | PMC10593799 | ||
Results | atrial fibrillation | ATRIAL FIBRILLATION, EVENTS, PAROXYSMAL ATRIAL FIBRILLATION | A total of 50 patients who met the inclusion criteria were included in this study, and all of them completed the requirements of the experimental protocol in a standardized manner, with no withdrawals. Among them, 15 were able to perform the CPET independently and complete it preoperatively. The 50 participants were randomly divided into the exercise and control groups, with 25 in each group. All participants participated in the 6-MWT to assess baseline and final mobilities and cardiorespiratory endurance before cardiac repair and after the intervention cycle (Fig. Flow charts of the procedures.One patient developed paroxysmal atrial fibrillation postoperatively, and the exercise intervention was performed during sinus rhythm, and atrial fibrillation did not recur. The test process was safe, and no adverse cardiovascular events occurred. | PMC10593799 |
CPET for 15 children in two groups | congenital heart disease | DISEASE | Statistical testing revealed no significant differences in the demographic, LVEF, preoperative 6MWD and disease types. The CPET results exhibited no significant differences in load at peak, VODemographic, LVEF, preoperative 6MWD, CPET and disease type of the total cohort and two groups.Data are expressed as the mean ± standard deviation or number (%).CHD, congenital heart disease; BMI, body mass index; LVEF, left ventricular ejection fraction; 6MWD, 6 min walk distance; VO | PMC10593799 |
The relationship of VO | Preoperative VOCorrelation analysis of VO2peak and 6-MWT pre-operatively. | PMC10593799 | ||
Exercise training in the two groups | ventricle septal defect, patent ductus arteriosus, bicuspid aortic valve, atrial septal defect | DISEASE | Statistical testing revealed no significant differences in the preoperative general demographic data, LVEF, and disease type of the exercise and control groups (Table Demographics, LVEF, and disease type of the total cohort and two groups.BMI, body mass index; LVEF, left ventricular ejection fraction; ASD, atrial septal defect; PDA, patent ductus arteriosus; VSD, ventricle septal defect; BAV, bicuspid aortic valve.There was no significant difference between the preoperative 6MWD of the exercise and control groups. After the intervention, the control group’s postoperative 6MWD was less than their preoperative 6MWD (376.56 ± 54.78 m vs. 347.12 ± 54.36 m; Comparison of the baseline and final 6MWD of the two groups.Baseline and final 6-MWT in the exercise and control groups. | PMC10593799 |
Author contributions | S.X. conceived the idea for the study. H.Z. led the work group. R.Q. drafted the text and provided editorial oversight. S.L. performed section of statistical analyses. H.W. provided editorial oversight. S.L./X.H./W.L./F.H. reviewed and commented on the final draft of the manuscript. R.Q./Y.Z./B.Y. co-led the work group. All authors agreed to the final version of the manuscript. | PMC10593799 | ||
Funding | Funding was provided by Henan Provincial Key R&D and Promotion Project (Grant Number 212102310788), Henan Province Medical Science and Technology Research Plan Joint Construction Project (Grant Number LHGJ20200733) and Hubei Provincial Engineering Research Centre of Vascular Interventional Therapy. | PMC10593799 | ||
Data availability | The datasets used and/or analyzed in this study are available from the corresponding author upon reasonable request. | PMC10593799 | ||
Competing interests | The authors declare no competing interests. | PMC10593799 | ||
References | PMC10593799 | |||
Abstract | PMC10209436 | |||
Background | human immunodeficiency virus type 1 (HIV-1) RNA | Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice-daily dolutegravir dosing when coadministered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed human immunodeficiency virus type 1 (HIV-1) RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE). | PMC10209436 | |
Methods | virologic failure | We conducted a randomized, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (2 consecutive HIV-1 RNA ≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA <50 copies/mL at week 24. This study was not powered to compare arms. | PMC10209436 | |
Results | One hundred thirty participants were randomized (65 to each arm). Median baseline HIV-1 RNA was 4.0 log | PMC10209436 | ||
Conclusions | Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. | PMC10209436 | ||
Clinical Trials Registration | toxic, breast cancer | BREAST CANCER | NCT03991013.Among adults switching to second-line tenofovir-lamivudine-dolutegravir with unsuppressed HIV-1 RNA levels and substantial baseline nucleoside reverse transcriptase inhibitor resistance, a high proportion achieved virologic suppression.Clinical Trials Registration. NCT03991013Dolutegravir with 2 nucleoside reverse transcriptase inhibitors (NRTIs) is the World Health Organization (WHO)–recommended second-line antiretroviral therapy (ART) regimen for adults failing first-line regimens based on the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine or efavirenz [Tenofovir is less toxic than zidovudine [Efavirenz induces drug metabolizing enzymes (UGT1A1 and CYP3A4) and transporters (P-glycoprotein and breast cancer resistance protein), which decreases dolutegravir exposure [We previously conducted a prospective cohort study of recycled tenofovir and lamivudine with dolutegravir in second-line ART with a supplementary dolutegravir dose (50 mg twice daily) for 2 weeks to overcome efavirenz induction, and 85% achieved virologic suppression at week 24, despite 65% having resistance to both tenofovir and lamivudine at baseline [ | PMC10209436 |
METHODS | PMC10209436 | |||
Study Design and Participants | virologic failure | ARTIST is a noncomparative, randomized, double-blind, placebo-controlled, phase 2, 48-week trial of second-line TLD with or without a lead-in supplementary dolutegravir dose in patients with virologic failure on first-line TEE. A detailed protocol describing our methods has been published [Eligible patients were adults (≥18 years old) with virologic failure (defined as 2 consecutive human immunodeficiency virus type 1 (HIV-1) RNA ≥1000 copies/mL 2–24 months apart) on a first-line regimen of tenofovir, emtricitabine (or lamivudine), and efavirenz. Exclusion criteria were CD4 | PMC10209436 | |
Randomization, Allocation Concealment, and Masking | Participants were randomly assigned (1:1) to a second-line regimen consisting of tenofovir (300 mg), lamivudine (300 mg), and dolutegravir (50 mg), given as a once-daily fixed-dose combination tablet, with an additional lead-in dose of dolutegravir (50 mg) or placebo taken 12 hours later for the first 14 days. An independent pharmacist generated the randomization sequence before trial commencement using block randomization (block size of 10). The study pharmacists used sequentially drawn individually sealed opaque envelopes to assign a treatment arm when dispensing medication. All participants and study staff involved in clinical care were blinded to treatment allocation. | PMC10209436 | ||
Procedures | Follow-up study visits with clinicians occurred at weeks 2, 4, 8, 12, 16, 20, and 24 (with a visit window of ±16 days at each visit except the week 24 visit, which had a window of ±6 weeks). Plasma HIV-1 RNA was measured at baseline and every visit from week 4 onward. If any HIV-1 RNA after week 12 was ≥50 copies/mL, or if there was <1 logCD4We monitored adherence with tenofovir diphosphate (TFV-DP) concentrations at baseline, 12 weeks, and 24 weeks, using stored dried blood spot specimens. An indirect method for the quantification of TFV-DP in 50 mL human dried blood spots was adapted from a previously described method [ | PMC10209436 | ||
Outcomes | virologic failure, AIDS, virologic suppression, intolerance or adverse event | ADVERSE EVENT, ADVERSE EVENTS, ADVERSE EVENT, AIDS, SECONDARY | The primary outcome was proportion with virologic suppression (defined as HIV-1 RNA <50 copies/mL) at week 24. We conducted a modified intention-to-treat (mITT) analysis according to the US Food and Drug Administration (FDA) snapshot approach, which defines failure as any 1 of HIV-1 RNA measurements ≥50 copies/mL, missing HIV-1 RNA within the window, intolerance or adverse event because of any study drug requiring switch, or loss to follow-up [The secondary outcomes included virologic suppression at week 12 (with the same definition as for the primary outcome), proportion with HIV-1 RNA <400 copies/mL at weeks 12 and 24 (mITT; FDA Snapshot), time to virologic suppression, emergence of resistance mutations in participants meeting protocol-defined criteria for GART, including those with virologic failure (defined as 2 consecutive HIV-1 RNA ≥1000 copies/mL after week 12), and proportion developing grade 3 or 4 adverse events and serious adverse events. Adverse events were evaluated and graded at all study visits according to the Division of AIDS Table for Grading the Severity of Adult and Paediatric Adverse Events [ | PMC10209436 |
Statistical Considerations | A sample size of 57 participants in each arm was estimated to produce a 95% confidence interval (CI) of 72%–92%, assuming the proportion achieving virologic suppression of 82% at week 24 (as achieved in the dolutegravir arm of the DAWNING study [ | PMC10209436 | ||
Ethics Approval | Written informed consent was obtained from all participants. This study was approved by the Human Research Ethics Committee at the University of Cape Town (Ref 039/2019). We registered the study protocol on ClinicalTrials.gov (NCT03991013). A trial steering committee with independent members provided trial oversight and an independent data and safety committee reviewed interim safety data every 2 months. | PMC10209436 | ||
RESULTS | death, human immunodeficiency virus type 1, psychosis, virologic failure, SAEs, acute kidney injury, insomnia, Insomnia, headache, coronavirus disease 2019 | PULMONARY TUBERCULOSIS, CORONAVIRUS DISEASE 2019, ADVERSE EVENTS, SENSITIVITY, ADVERSE EVENT, HUMAN IMMUNODEFICIENCY VIRUS TYPE | Participants were recruited between 28 August 2020 and 10 November 2021. Of 178 adults screened, 130 participants were randomly assigned to receive lead-in supplementary dolutegravir (n = 65) or placebo (n = 65) (Eligibility assessment, randomization, treatment, and follow-up. *Eight patients had CD4 count <100 cells/µL and 3 had CD4 count <50 cells/µL. The protocol was amended to broaden the CD4 inclusion criterion from ≥100 to ≥50 cells/µL on 14 July 2021. Baseline CharacteristicsAbbreviations: ART, antiretroviral therapy; BMI, body mass index; DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; IQR, interquartile range; NRTI, nucleoside reverse transcriptase inhibitor; TFV-DP, tenofovir diphosphate; TLD, tenofovir-lamivudine-dolutegravir; XTC, lamivudine or emtricitabine.Resistance was classified with the Stanford algorithm, with a score of ≥15 indicating at least low-level resistance.Denominators indicate the numbers of participants with available viral sequences.Both NRTIs had a Stanford score <15 indicating susceptibility or only potential of low-level resistance.Virologic outcomes by study arm at weeks 12 and 24 are shown in Summary of Plasma Human Immunodeficiency Virus Type 1 RNA OutcomesAbbreviations: CI, confidence interval; DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; mITT, modified intention-to-treat; TLD, tenofovir-lamivudine-dolutegravir.mITT analysis excludes those switching study drug for reasons of stopping contraception or desire to become pregnant, becoming pregnant, transfer out for nonclinical reasons, and death from non-HIV and nondrug causes.Sensitivity analysis excludes those excluded from mITT analysis, as well as loss to follow-up, missing viral load within the window, switching study drug for reasons other than treatment failure, and evidence of poor adherence (tenofovir diphosphate <350 fmol/punch).One-sided 97.5% CI when 0 or 100% were successful.In the subgroup with resistance to both tenofovir and lamivudine at baseline, virologic suppression at week 24 was achieved by 39 of 45 (87% [95% CI: 73%–95%]) participants in the supplementary dolutegravir arm and 36 of 45 (80% [95% CI: 65%–90%]) participants in the placebo arm. Time to virologic suppression by arm is shown in Kaplan-Meier for time to virological suppression (human immunodeficiency virus type 1 RNA <50 copies/mL). Abbreviations: DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; TLD, tenofovir-lamivudine-dolutegravir.Six participants (3 in each arm) met protocol-defined criteria for GART by week 24; no participants developed dolutegravir resistance or acquired new resistance mutations to tenofovir or lamivudine. One participant in the supplementary dolutegravir arm developed virologic failure at week 16; GART detected no integrase resistance mutations and the participant reported poor adherence (corroborated by TFV-DP concentration <350 fmol/punch at week 12). There were 19 participants with HIV-1 RNA ≥50 copies/mL at week 24; 15 of 19 (79%) later resuppressed HIV-1 RNA <50 copies/mL with enhanced adherence counseling.Median increase in CD4Tenofovir diphosphate (TFV-DP) concentrations at baseline, 12 weeks, and 24 weeks (boxes indicate interquartile range, horizontal solid lines are medians, vertical lines are ranges, and solid circles are outliers). Dotted lines refer to TFV-DP concentrations categorized using the threshold defined by Anderson et al [Grade 3 or 4 adverse events and serious adverse events were uncommon (Proportion of participants with a ≥1-unit increase in the Insomnia Severity Index (ISI) and reported insomnia as an adverse event. Sleep was evaluated using the ISI, a 7-item tool with a total score ranging from 0 to 28. A higher score indicates a worse performance. Numerator is the number of individuals who reported insomnia with at least a 1-unit increase in ISI score from baseline (week 0). Denominator is the number of individuals with an ISI score at each week for all individuals with a baseline result. Abbreviations: DTG, dolutegravir; TLD, tenofovir-lamivudine-dolutegravir.Number (%) of Participants With Adverse EventsAbbreviations: AE, adverse event; DTG, dolutegravir; SAE, serious adverse event; TLD, tenofovir-lamivudine-dolutegravir.The death in the DTG arm was caused by severe coronavirus disease 2019 (COVID-19).The SAEs in the DTG arm were severe COVID-19 leading to death, and acute psychosis, which was considered unrelated to the study drug and resolved without discontinuation of the study drug.The grade 3 AEs in the DTG arm were acute psychosis and incident pulmonary tuberculosis. The grade 3 AEs in the placebo arm were raised random glucose (experienced by 2 participants), acute kidney injury (experienced by 2 participants), and headache.One participant in the placebo arm switched from tenofovir to zidovudine after developing a creatinine elevation. | PMC10209436 |
DISCUSSION | virologic failure, TLD, insomnia | DRUG INTERACTION | In our study, second-line TLD produced acceptable rates of virologic suppression at 24 weeks in adults with virologic failure on first-line TEE, with and without a lead-in supplementary dolutegravir dose. No emergent dolutegravir resistance occurred over 24 weeks among our cohort of patients who switched with unsuppressed HIV-1 RNA levels, despite the majority having resistance to both tenofovir and lamivudine at baseline. Our findings strengthen the evidence base for recycling tenofovir and lamivudine with dolutegravir in second-line ART in resource-limited settings.Our results are consistent with those from previous randomized controlled trials assessing the efficacy of dolutegravir in second-line ART [A previous study conducted among healthy, HIV-negative volunteers showed that efavirenz reduced dolutegravir trough concentrations by 75% when coadministered, but that doubling the dolutegravir dose mitigated the drug–drug interaction [Emergent dolutegravir resistance has been documented infrequently in second-line ART (4% at 96 weeks in NADIA, and 2% at 159 weeks in DAWNING) [In ARTIST, we observed a substantial incidence of insomnia (13%) reported by participants at week 2 with no discernible difference in the proportion between arms; the majority of insomnia complaints were mild and did not reach clinical significance based on ISI scores, and 76% resolved by week 4. The incidence of insomnia we found is twice that reported in a meta-analysis of trial participants randomized to dolutegravir [Our study has limitations. First, our study was not powered to formally assess differences between arms. Although the sample size did not allow for a statistically powered comparison, our study was designed to rapidly generate data to supplement the findings from NADIA [ | PMC10209436 |
CONCLUSIONS | The ARTIST study provides additional evidence that maintaining tenofovir and lamivudine with dolutegravir is effective and well tolerated in second-line ART. Our results provide evidence over 24 weeks that patients with unsuppressed HIV-1 RNA levels on first-line TEE can safely switch to second-line TLD without a lead-in supplementary dolutegravir dose to overcome efavirenz induction—however, it is possible that resistance will emerge at later timepoints. | PMC10209436 | ||
Notes | PMC10209436 | |||
References | PMC10209436 | |||
Key Points | PMC10548310 | |||
Question | dementia | Do physicians prioritize different ethical considerations when considering deprescribing medications for older adults (aged ≥65 years) with dementia? | PMC10548310 | |
Findings | dementia | ADVERSE DRUG EVENT | In this national survey study of 890 primary care physicians, 9 factors influencing deprescribing decisions for older adults with dementia were prioritized. When a medication may increase risk of an adverse drug event or have limited benefit as a treatment, physicians are sensitive to concerns that deprescribing would worsen symptoms, are more reluctant to deprescribe a medication started by someone else, and less concerned about the cost of medication. | PMC10548310 |
Meaning | dementia | Results of this survey study suggest that managing symptoms and well-being and working with other clinicians are priorities for clinicians managing medications for older adults with dementia. | PMC10548310 | |
Importance | dementia | Physicians endorse deprescribing of risky or unnecessary medications for older adults (aged ≥65 years) with dementia, but there is a lack of information on what influences decisions to deprescribe in this population. | PMC10548310 | |
Objective | dementia | To understand how physicians make decisions to deprescribe for older adults with moderate dementia and ethical and pragmatic concerns influencing those decisions. | PMC10548310 | |
Design, Setting, and Participants | A cross-sectional national mailed survey study of a random sample of 3000 primary care physicians from the American Medical Association Physician Masterfile who care for older adults was conducted from January 15 to December 31, 2021. | PMC10548310 | ||
Main Outcomes and Measures | dementia | REGRESSION, ADVERSE DRUG EVENT | The study randomized participants to consider 2 clinical scenarios in which a physician may decide to deprescribe a medication for older adults with moderate dementia: 1 in which the medication could cause an adverse drug event if continued and the other in which there is no evidence of benefit. Participants ranked 9 factors related to possible ethical and pragmatic concerns through best-worst scaling methods (from greatest barrier to smallest barrier to deprescribing). Conditional logit regression quantified the relative importance for each factor as a barrier to deprescribing. | PMC10548310 |
Results | A total of 890 physicians (35.0%) returned surveys; 511 (57.4%) were male, and the mean (SD) years since graduation was 26.0 (11.7). Most physicians had a primary specialty in family practice (50.4% [449 of 890]) and internal medicine (43.5% [387 of 890]). A total of 689 surveys were sufficiently complete to analyze. In both clinical scenarios, the 2 greatest barriers to deprescribing were (1) the patient or family reporting symptomatic benefit from the medication (beneficence and autonomy) and (2) the medication having been prescribed by another physician (autonomy and nonmaleficence). The least influential factor was ease of paying for the medication (justice). | PMC10548310 | ||
Conclusions and Relevance | dementia | Findings from this national survey study of primary care physicians suggests that understanding ethical aspects of physician decision-making can inform clinician education about medication management and deprescribing decisions for older adults with moderate dementia.This survey study of primary care physicians assesses the prioritization of different ethical considerations when considering deprescribing medications for older adults with dementia. | PMC10548310 | |
Introduction | dementia, cognitive impairment | DRUG INTERACTIONS, ADVERSE DRUG EVENTS, ADVERSE EFFECTS | Deprescribing has been defined in several studiesFurther, these ethical dilemmas related to optimal prescribing arise ubiquitously for clinicians treating people living with dementia who are particularly vulnerable to serious harm from polypharmacy (adverse drug events or drug interactions), treatment burden, and cognitive changes from adverse effects.Clinicians have little evidence to guide deprescribing decisions due to a clinical research culture focused on generating evidence to inform treatment intensification and methodologic limitations to conducting deprescribing investigations at scale. Without guidelines, clinicians may feel alone in their decision-making and have expressed reservations about stopping or reducing medicines. Articulated areas of uncertainty include changing medications started by other clinicians and having insufficient evidence on tapering and stopping medications.Understanding the influences on clinician decision-making in the context of potential ethical tensions and patient-centered pragmatic decision-making may help prepare clinicians for deprescribing discussions with their patients. In addition, understanding common deprescribing practices may inform the research agenda and support clinicians in undertaking thoughtful deprescribing until a formal evidence base becomes available.This study aimed to understand influences on physician deprescribing decision-making. To help guide development of deprescribing guidance and clinician education, we surveyed a national sample of primary care physicians who care for older adults (aged ≥65 years) on perceived influences affecting their deprescribing decisions for persons with cognitive impairment. | PMC10548310 |
Methods | PMC10548310 | |||
Study Design and Sample | We mailed a self-administered 24-question survey entitled “Understanding Physician Deprescribing Decisions” (eMethods in | PMC10548310 | ||
Survey Development | The survey was designed around 2 common scenarios in which clinicians may consider deprescribing: situations in which treatment presented an increased risk of an ADE and situations in which treatment would produce limited benefit ( | PMC10548310 | ||
Clinical Scenarios and Bioethical and Pragmatic Factors for Best-Worst Scaling Questions | fracture, dementia, BWS | ADVERSE DRUG EVENT | Deprescribing scenarios: (1) increased risk of ADE: “There is evidence for increased risk of a serious acute adverse drug event (eg, fall or fracture) that could happen at any time if this drug is continued,” and (2) limited benefit: “There is no evidence of benefit for this medication in the older adult dementia population.”We used the best-worst scaling (BWS) method to assess respondents’ rankings of perceived barriers to deprescribing a medication in this population.Best-worst scaling was chosen because the task is known to be easily understood by respondents, and because it asks the respondent to make comparisons over multiple sets of questions instead of 1 single set. | PMC10548310 |
Survey Administration and Data Collection | Using the Dillman tailored design method for mailed surveys, | PMC10548310 | ||
Statistical Analysis | BWS | REGRESSION | Descriptive statistics were used to present self-reported demographic responses. We performed conditional logit regression to analyze the BWS questions because it is grounded in random utility theory and explains real-world choice behaviors.We also calculated individual best-minus-worst scores based on the difference between the number of times a factor was selected as the biggest barrier and the number of times it was selected as the smallest barrier. The range of scores was −4 to 4 as each phrase appeared equally in 4 of the 12 choice sets. We used best-minus-worst scores to examine variability in barrier ratings by estimating how often and how consistently each barrier was selected as the most or least important factor. For all analyses, we excluded respondents with missing or invalid choices. The answer to each block counted as 2 choices (biggest barrier and smallest barrier). Choices were designated as invalid if respondents chose more than 1 phrase as the biggest barrier or smallest barrier, if they chose the same phrase as the biggest barrier and smallest barrier, or if they did not choose a phrase as the biggest barrier or smallest barrier. All analyses were conducted using SAS version 9.4 (SAS Institute Inc). | PMC10548310 |
Results | PMC10548310 | |||
Respondent Characteristics | Of the 3000 invited physicians, 454 were excluded as undeliverable or ineligible (ie, retired, deceased, or no longer practicing medicine); of 2546 who were presumed to receive surveys, 890 physicians returned surveys (511 [57.4%] were male, and the mean [SD] years since graduation was 26.0 [11.7]), giving a response rate of 35.0% (890 of 2546) ( | PMC10548310 | ||
Survey Flowchart | SECONDARY | The eligibility specified for the 2 random samples were identical. The difference between the denominator for 2 random sample populations is due to the changes/updates to the American Medical Association Physician Masterfile at each date (ie, more physicians becoming eligible at a later date in 2021). Eligible physicians were primary care clinicians with a mailing address in any US state (territories not included) and could have a primary specialty in family practice, general practice, internal medicine, family practice–geriatrics, internal medicine–geriatrics, or geriatric psychiatry and/or a secondary specialty in the same primary specialty categories. USPS indicates United States Postal Service.The demographic characteristics of respondents vs nonrespondents from the AMA data set are shown in eTable 1 in | PMC10548310 | |
Self-Reported Characteristics of Respondents Included in Analyses | ADVERSE DRUG EVENT | Abbreviation: ADE, adverse drug event.No significant differences were observed between the 2 different survey groups (increased risk of ADE vs limited benefit), and the number of responses varied between 681 and 689 given that some respondents did not answer all questions. | PMC10548310 | |
Relative Importance of 9 Barriers That May Influence a Physician’s Decision to Deprescribe a Medicine in an Older Adult With Moderate Dementia | ADVERSE DRUG EVENT | A phrase was assigned a value of −1 if chosen as the smallest barrier and 1 if chosen as the biggest barrier. We set the smallest barrier (perceived as the least important) as the reference at 1 so that a phrase with a relative preference of 2 means the phrase/barrier was perceived as twice as important compared with the reference phrase/barrier. Error bars indicate 95% CIs. ADE indicates adverse drug event. | PMC10548310 | |
Variability of Perceived Barriers Between Individual Physicians | ADVERSE DRUG EVENT | This figure shows the number of times each phrase/barrier was chosen as the biggest and smallest barrier to deprescribing a medication (across the series of 12 sets of 3 phrases/barriers presented to each respondent) and ranked from biggest (right) to smallest barrier (left). Each phrase/barrier was presented 4 times to each participant, so the maximum number of times it could be chosen as the biggest or smallest barrier was 1368 (342×4) for scenario 1 and 1388 (347×4) for scenario 2. ADE indicates adverse drug event. | PMC10548310 | |
Discussion | dementia | We conducted a national survey study exploring how primary care physicians prioritize barriers linked to several ethical and pragmatic considerations when making deprescribing decisions in caring for older individuals living with moderate dementia. To our knowledge, this is the first exploration of how ethical considerations affect physician deprescribing. We found that when a medication is known to have an increased risk of an ADE or has limited to no benefit as a treatment, physicians are particularly sensitive to patient or family member concerns about deprescribing (that is, autonomy). Physicians also appear to be reluctant to interfere with their colleagues’ medical management and deprescribe a medication started by someone else (autonomy and nonmaleficence) and are much less concerned about the financial impact of continuing or discontinuing a medication (justice). Overall, barriers related to the ethical principle of justice appeared to be less important barriers than those related to beneficence, nonmaleficence, and autonomy.In both clinical scenarios, our findings that physicians view symptom management as the most important barrier to deprescribing aligns with a previous national physician survey of cardiologists, general internists, and geriatricians trying to deprescribe cardiovascular medications in older adults.Our finding that physicians view medications being prescribed by other specialists/colleagues as a major barrier to deprescribing bolsters similar findings in other recent physician and primary care clinician surveys on deprescribing cardiovascular medicationsOur finding that physicians consider the financial impact of continuing or discontinuing a medicine as the least important barrier to deprescribing may provide an alternative entry point to starting conversations about deprescribing with their patients and may require clinician education. As highlighted by Hung et al,Overall, our findings have implications for physicians and future research. By linking barriers to ethical principles, physicians will be able to reflect on what might be behind the barriers they experience and explore whether they are allowing a single principle, such as autonomy, to dominate their decision-making. This work may inform research aimed at developing guidance on how ethical principles can be used as a framework to support decision-making around deprescribing, especially when there is a lack of evidence to inform the likely benefits and harms of deprescribing certain medications in complex situations. Given the finding that factors related to nonmaleficence do appear to play a large role in deprescribing decision-making, future research could explore how this could be used as a trigger for deprescribing. In qualitative studies,Our work may also inform future designs of deimplementation interventions to deprescribe inappropriate medications. For example, a common physician-level characteristic that affects deimplementation is past negative experiences. | PMC10548310 | |
Strengths and Limitations | dementia, Alzheimer disease | ADVERSE EFFECTS, ALZHEIMER DISEASE | Our national survey study of physicians had some key strengths. First, the survey used BWS methods to elicit respondent preferences in a complete ranking as compared with Likert scale methods. Second, the survey was conducted and framed around a particularly relevant and vulnerable patient population that is at great risk of adverse effects of polypharmacy. Third, our study focused on primary care for older adults with Alzheimer disease and related dementia, which has been identified as a research priority and clinical need.Given the importance of symptom management as a barrier to deprescribing, there is a need for greater access to nonpharmacological approachesOur study also had several limitations. First, the study was conducted during the COVID-19 pandemic, and this may have influenced physicians’ responses as they relate to the care of individuals living with Alzheimer disease and related dementia. Second, our response rate was in the middle range for contemporary physician surveys, which raises the potential for response bias. However, given similar response rates to other survey studies conducted recently, | PMC10548310 |
Conclusions | dementia | Understanding ethical aspects of physician decision-making can inform clinician education about medication management and deprescribing decisions for older adults with moderate dementia. This research highlights that clinician education on deprescribing should include shared decision-making to prioritize goals of care and patient symptom management and that clinician-to-clinician communication is essential. Further research on the most effective tools and strategies is needed. Addressing these barriers through deprescribing strategies and educational initiatives will be important to reduce medication-related harm in older adults living with dementia. | PMC10548310 | |
Background | OHCA, cardiac arrest | CARDIAC ARREST | Telephone-Cardiopulmonary Resuscitation (T-CPR) significantly increases rate of bystander resuscitation and improves patient outcomes after out-of-hospital cardiac arrest (OHCA). Nevertheless, securing correct execution of instructions remains a difficulty. ERC Guidelines 2021 recommend standardised instructions with continuous evaluation. Yet, there are no explicit recommendations on a standardised wording of T-CPR in the German language. We investigated, whether a modified wording regarding check for breathing in a German T-CPR protocol improved performance of T-CPR. | PMC10067171 |
Methods | OHCA | A simulation study with 48 OHCA scenarios was conducted. In a non-randomised trial study lay rescuers were instructed using the real-life-CPR protocol of the regional dispatch centre and as the intervention a modified T-CPR protocol, including specific check for breathing (head tilt-chin lift instructions). Resuscitation parameters were assessed with a manikin and video recordings. | PMC10067171 | |
Results | Check for breathing was performed by 64.3% ( | PMC10067171 | ||
Conclusion | Correct check for breathing seems to be a problem for lay rescuers, which can be decreased by describing the assessment in more detail. Hence, T-CPR protocols should provide standardised explicit instructions on how to perform airway assessment. Each protocol should be evaluated for practicability.
| PMC10067171 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10067171 | ||
Background | OHCA, cardiac arrest | CARDIAC ARREST | Out-of-hospital cardiac arrest (OHCA) is a worldwide common condition with a global incidence of 83.7/100,000 per year [Instructions to check for breathing prove to be particularly difficult in T-CPR protocols [ | PMC10067171 |
Methods | PMC10067171 | |||
Study design | This controlled non-randomised trial was part of the exploratory observational project MV|LIFE|DRONE-Pilot, funded by the German Federal Ministry of Health and approved by the Ethics Committee of Greifswald University (BB124/19). In each simulation, lay rescuers were instructed with T-CPR to resuscitate. | PMC10067171 | ||
Participants | OHCA | The lay rescuers were recruited through media as well as word-of-mouth communication. Participation in the study and the collection of anonymous data was based on obtaining written informed consent from all participants. Lay rescuers were informed they would encounter a simulated OHCA and would have to resuscitate for a maximum of 15 min. To avoid bias, no further information was given. Exclusion criteria for participation were physical limitations, resuscitation training within the past five years and no written consent. Each lay rescuer participated only once. | PMC10067171 | |
Measurement and data sources | chest compression | EVENT | The simulation room was equipped with two cameras, which recorded every event in image and sound. The execution of each step of the dispatcher's instructions was measured categorically by analysing the simulation videos. To investigate the impact of the wording of check for breathing instruction the original T-CPR protocol as used by the regional dispatch centre was compared to a modified instruction on assessing breathing. The original check for breathing instruction was used in simulation 1–20 and the modified check for breathing instruction was used in simulation 21–48. In simulations 1–20 (original wording group) the wording from the protocol was: “Is he/she breathing normally? “. In simulation 21–48 (intervention group), check for breathing was specified using the following question: “When you tilt the head backward, does the chest rise and fall?”. No further parts of the protocol were changed. The entire protocol can be viewed in Fig. Telephone-cardiopulmonary resuscitation protocolLaerdal's Resusci Anne QCPR MK II was used as the resuscitation simulator with a wireless connected SimPad® Plus from Laerdal™. The SimPad® Plus assesses compression depth (in mm), chest compression frequency (in bpm) and chest release (0% (no release)—100% (complete release)). The resuscitation data were averaged and processed using MATLAB® R2020b (MathWorks, Natick, USA). Hand position was also evaluated using the videos and was scored as sufficient if the heel of the hand was in a 9 × 9 cm square on the centre of the chest. | PMC10067171 |
Bias | During the scenarios T-CPR was instructed by an emergency physician, who had been trained in T-CPR by a dispatcher before the first session of the study. To avoid bias the simulated dispatcher was not aware of the study hypothesis and was located in a different room. He did not see the rescuers and communication was possible only via telephone. Also, to avoid bias, the T-CPR protocol was instructed live, following real-life standards (Fig. | PMC10067171 | ||
Study size | Sample size of our study ( | PMC10067171 | ||
Statistical methods | ® | Statistical evaluation were performed with SPSS® Statistics Version 27 (IBM Corporation Armonk, New-York, USA). Graphs were created using Prism 9® (GraphPad Software Inc., Boston, USA). Descriptive representation of nominal variables is presented with numbers (n) and valid percentages (%). Normal distribution was determined using Shapiro–Wilk test. Cluster comparison was presented using the chi-square test. If the expected frequency of data was below 5, Fisher's exact test was applied. Quantitative data were reported with mean value, standard deviation and were compared using the Mann–Whitney U test. The | PMC10067171 | |
Results | A total of 48 resuscitation simulations with 48 lay rescuers were conducted. Because of missing SimPad® data and discontinuation of the simulation by participants, seven simulations had to be excluded. As a result, 41 simulations were available for analysis.The anonymous survey which followed the simulation was not completed by 3 lay rescuers. All other questionnaires (45 data sets) were included in the analysis (Table Gender and age of study participantsLegend: | PMC10067171 | ||
Quality of execution of T-CPR instructions | Table Execution of the T-CPR instructions | PMC10067171 | ||
Quality of chest compressions | Specified, Specified Chest compression | The mean chest compression rate did not differ significantly between groups and was 103.1 ± 14.0 bpm in the intervention group and 91.5 ± 17.2 bpm in the original wording group (CPR-QualityInitialOriginal Specified 0 – 1 MinOriginal Specified 1 – 2 MinOriginal Specified 2 – 3 MinOriginal Specified TotalOriginal Specified Chest compression frequency for both groups in beats per minute (numbers of participants in squares)Compression depth for both groups in millimetres (numbers of participants in squares) | PMC10067171 | |
Discussion | PMC10067171 | |||
Quality of execution of T-CPR instructions | SECONDARY | Significantly fewer lay rescuers (64.3%) performed a check for breathing in the original wording group in comparison with the specified instruction (92.6%) asking for head tilt-chin lift. In the intervention group the head tilt-chin lift manoeuvre was performed significantly more often and the time duration for check for breathing was appropriate. According to the ERC guidelines the check for breathing including looking, listening and feeling for breathing should take no more than 10 s [The secondary study hypothesis of a prolonged time until start of chest compression with introduction of the modified wording could not be confirmed. The time interval from beginning of the emergency call to start of CPR was significantly longer with original wording (95 ± 33 s.) compared to the specified wording (80 ± 25 s.). Both groups started chest compression earlier than in a corresponding study of the Bavarian telephone resuscitation algorithm 2013 with 202 s [In comparison with the study by Klotz using the Bavarian telephone resuscitation protocol (46/46 = 100%) slightly fewer lay rescuers performed a consciousness check in our study (original wording group: 85.7% vs. intervention group 100%) [It can be noticed that a single lay rescuer who did not remove the clothing had already started CPR before the T-CPR instructions were given. There is no standardised wording for ongoing CPRs in the existing protocol. Hardeland and colleagues analysed data from the emergency dispatch centres of Copenhagen, Stockholm and Oslo and showed, that in cases, where CPR was already initiated, dispatchers were less likely to provide instructions [ | PMC10067171 | |
Quality of CPR | chest compression | The mean chest compression frequency did not differ significantly between both groups. Plata et al. also showed non-guideline compliant chest compression frequencies in a randomised controlled simulated T-CPR manikin trial with 78 bpm [The average compression depth over the entire time was lower in the original wording group compared to the intervention group. The compression depth was not part of the study's hypothesis, so this significance may have been due to cumulative alpha error and missing Bonferroni correction.Nearly all participants in both groups had a correct hand position. The wording of the T-CPR protocol "in the middle of the chest" is thus practicable and confirms the results of Lee et al. [ | PMC10067171 | |
Limitation | OHCA, cardiac arrest | CARDIAC ARREST | The foremost limitation results from the chosen study design, which is a non-randomized simulation trial. The present study was part of a large feasibility study. Due to this, randomisation was not possible. The study design as a non-randomised trial study is a limitation. We have to assume that mainly participants with primary interest in the topic came forward. Since participants were aware, that they would encounter a simulated cardiac arrest, an expectation bias with a potential positive effect on the execution quality must be considered. Participants were less surprised and most likely had lower stress levels. Due to study design the dispatcher knew, that the caller would describe a person in OHCA, which reduced the time until recognition of OHCA. Therefore, sensitivity and specificity of the algorithm regarding cardiac arrest recognition were not evaluated. Increasing the accuracy of OHCA recognition is a topic of ongoing research [ | PMC10067171 |
Conclusions | chest compression | Most of the instructions given in the T-CPR protocol were executed adequately. However, check of consciousness was a difficulty for the participants in the original wording group. With the specified wording including head tilt-chin lift instructions check for breathing was carried out significantly more adequately. It could be shown, that detailed instructions for check for breathing should be used to avoid difficulties in understanding. To improve chest compression frequency the dispatcher should continuously count out loud or transmit the clicking of a metronome. To reach the full potential of T-CPR wording of every T-CPR protocol should be evaluated regarding comprehension and practicability. | PMC10067171 | |
Acknowledgements | We would like to thank Dr Karl Thies, Dr Tobias Kozlowski and Dr Jan Bartels for their medical and technical support in carrying out the study. We especially thank all the study participants. | PMC10067171 | ||
Authors’ contributions | CM | MB has contributed to: Conceptualisation, Methodology, Investigation, Project administration, Funding acquisition, Review and Editing. KH has contributed to: Conceptualisation and Funding acquisition. CM, BM and PB have contributed to: Methodology, Review and Editing. CRH has contributed to: Methodology, Formal analysis, Investigation, Writing—Original Draft and Visualisation. All authors read and approved the final manuscript. | PMC10067171 | |
Funding | Open Access funding enabled and organized by Projekt DEAL. The project MV|LIFE|DRONE-Pilot was funded by the German Federal Department of Health (ZMVI1-2519FEP006). The study sponsor was not involved in the study design, collection, analysis, interpretation of data or the writing of the manuscript and the decision to submit for publication. | PMC10067171 | ||
Availability of data and materials | The datasets used and analysed during the current study are available from the corresponding author on reasonable request. | PMC10067171 | ||
Declarations | PMC10067171 | |||
Ethics approval and consent to participate | All methods were carried out in accordance with the relevant guidelines and regulations and all participants submitted their informed consent in written form. The ethics committee of University Greifswald approved the study on 2019–09-26 (BB124/19). | PMC10067171 | ||
Consent for publication | Not applicable. | PMC10067171 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10067171 | ||
References | PMC10067171 | |||
Background | ambulatory diabetes, hypertensive | Medication reconciliation is an evidence-based practice that reduces medication-related harm to patients. This study evaluated the effect of educational intervention on medication reconciliation practice of pharmacists among ambulatory diabetes and hypertensive patients. | PMC10652589 | |
Methods | hypertensive, intervention-46, diabetes | DIABETES | A non-randomized clinical trial on medication reconciliation practice was carried out among 85 and 61 pharmacists at the intervention site and control site, respectively. Medication reconciliation was carried out among 334 (intervention-183; control-151) diabetes and/or hypertensive patients by the principal investigator to indirectly evaluate pharmacists’ baseline medication reconciliation practice at both sites. A general educational intervention was carried out among intervention pharmacists. Medication reconciliation was carried out by the principal investigator among another cohort of 96 (intervention-46; control-50) and 90 (intervention-44; control-46) patients at three and six months postintervention, respectively, to indirectly assess pharmacists’ postintervention medication reconciliation practice. Thereafter, a focused educational intervention was carried out among 15 of the intervention pharmacists. Three experts in clinical pharmacy analysed the medication reconciliation form filled by the 15 pharmacists after carrying out medication reconciliation on another cohort of 140 patients, after the focused intervention. Data was summarized with descriptive (frequency, percentage, mean ± standard deviation) and inferential (Pearson product-moment correlations analysis, independent-samples t-test and one-way ANOVA) statistics with level of significance set at | PMC10652589 |
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