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Assessments | RTT | SECONDARY | Coprimary and key secondary efficacy assessments using the RSBQ, the CGI-I scale and the CSBS-DP-IT Social Composite score were completed at baseline (except the CGI-I scale) and at each visit (weeks 2, 6 and 12 (or end of treatment)). The RSBQ is a caregiver-completed scale assessing key symptoms of RTT | PMC10287558 |
Efficacy endpoints | SECONDARY | Coprimary endpoints were the change from baseline to week 12 in RSBQ total score and the CGI-I scale score at week 12. The key secondary endpoint was the change from baseline to week 12 in the CSBS-DP-IT Social Composite score. A prespecified subgroup analysis examined treatment effects by age, baseline RSBQ severity and | PMC10287558 | |
Post hoc efficacy analyses | TEAE, diarrhea | Two additional efficacy analyses were conducted post hoc: CGI-I scale responders (scores ≤3) at week 12 and coprimary endpoints assessed in the presence or absence of the most commonly reported TEAE of diarrhea. | PMC10287558 | |
Statistical analysis | SECONDARY | A sample size of 184 participants (92 per group) was planned to provide 90% power for both coprimary endpoints combined with a two-sided significance level of 0.05. Efficacy was assessed in the full analysis set (received at least one dose and had a baseline value and at least one post-baseline value for the RSBQ or the CGI-I score); the safety analysis set consisted of participants who received at least one dose.Coprimary and key secondary efficacy endpoints were analyzed using the MMRM method assuming data missing at random. The MMRM included randomization strata of age group and baseline RSBQ severity score, baseline RSBQ (for RSBQ analysis), baseline CGI-S (for CGI-I scale analysis) and baseline CSBS-DP-IT Social Composite score (for the key secondary endpoint), treatment, visit, treatment-by-visit interaction and baseline-by-visit interaction as fixed effects and participant as a random effect; an unstructured covariance matrix modeled within-participant errors. The Kenward–Roger method was used for calculating denominator degrees of freedom for tests of fixed effects. Each coprimary endpoint was considered positive if | PMC10287558 | |
Reporting summary | Further information on research design is available in the | PMC10287558 | ||
Online content | Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02398-1. | PMC10287558 | ||
Supplementary information |
Supplementary Tables 1 and 2.Reporting SummaryFinal version of the statistical analysis plan.Final version of the study protocol. | PMC10287558 | ||
Source data |
Clinical study report.Clinical study report.Clinical study report.Clinical study report.Clinical study report.Clinical study report.Clinical study report.Clinical study report.Clinical study report. | PMC10287558 | ||
Extended data | PMC10287558 | |||
Alanine Aminotransferase Values. | Figure footnote: The dashed vertical line at day 1 indicates when study treatment was initiated.
| PMC10287558 | ||
Extended data | is available for this paper at 10.1038/s41591-023-02398-1. | PMC10287558 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02398-1. | PMC10287558 | ||
Acknowledgements | P., UC | HAAS | We thank the trial participants, their families and our fellow investigators involved in this trial: B. Suter (Texas Children’s Hospital, Houston, Texas, US), C. Buhrfiend, P. Heydemann (Rush University Children’s Hospital, Chicago, Illinois, US), S. Standridge, E. Broomall, K. Peariso (Cincinnati Children’s Hospital Medical Center, Division of Neurology and University of Cincinnati, College of Medicine, Department of Pediatrics, Cincinnati, OH, US), C. Fu, S. Peters (Vanderbilt University Medical Center, Nashville, Tennessee, US), R. Haas, N. Guido-Estrada (University of California, San Diego, La Jolla, California, US), S. Kessler, S. Massey (Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, US), A. Ananth (University of Alabama at Birmingham, Birmingham, Alabama, US), R. Ryther, J. Weisenberg (Washington University School of Medicine, Saint Louis, Missouri, US), D. Lieberman, R. Witt, D. Friedman (Boston Children’s Hospital Harvard Medical School, Boston, Massachusetts, US), A. Stratton (Children’s Hospital Colorado, Aurora, Colorado, US), V. Narayanan, N. Belnap (Translational Genomics Research Institute, Phoenix, Arizona, US), R.J. Hagerman, B. Restrepo, M. Jones* (UC Davis MIND Institute, Sacramento, California, US; *investigator passed away before participating in the trial), S.A. Skinner (Greenwood Genetic Center, Greenwood, South Carolina, US), T. Feyma, A. Beisang (Gillette Children’s Specialty Healthcare, Saint Paul, Minnesota, US), A. Djukic (Montefiore Medical Center, Children’s Hospital at Montefiore, Bronx, New York, US), Y. Shiloh-Malawsky, D. Cejas, Z. Fan (the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, US), R. Saneto (Seattle Children’s, Seattle, Washington, US), J. Ranells, A. Sanchez-Valle, C. Griffith, K. Morgan (University of South Florida Children’s Medical Services, Tampa, Florida, US), C. Smith-Hicks, M. Jain (Kennedy Krieger Institute, Clinical Trials Unit, Baltimore, Maryland, US), S. Parikh, G. Hsich (Cleveland Clinic, Cleveland, Ohio, US), A.L. Talboy, R. Sanchez (Emory Genetics Clinical Trial Center, Atlanta, Georgia, US). We also thank K. Raudibaugh, K. O’Rourke-Kosko, C. Murphy and R. Nunez of Acadia Pharmaceuticals. The study was funded by Acadia Pharmaceuticals. The study sponsor (Acadia Pharmaceuticals) contributed to the study design, the writing of the report and the decision to submit the article for publication. Medical writing support was provided by S. Murray, MSc, CMPP, of Evidence Scientific Solutions and funded by Acadia Pharmaceuticals. | PMC10287558 |
Author contributions | The sponsor, Acadia Pharmaceuticals, and J.L.N., A.K.P., T.A.B., E.M.B.-K. and D.G.G. conceived and designed the study; all authors conducted the study and collected data, performed the formal analysis, participated in data interpretation, critically revised the manuscript content for important intellectual content, approved the final version and agreed to be accountable for all aspects of the work. | PMC10287558 | ||
Peer review | PMC10287558 | |||
Data availability | This clinical trial was sponsored by Acadia Pharmaceuticals. Acadia supports data sharing consistent with the Principles for Responsible Clinical Trial Data Sharing and International Committee of Medical Journal Editors’ recommendations. Acadia shares data from completed clinical trials through public registries ( | PMC10287558 | ||
Competing interests | Rett Syndrome | RETT SYNDROME | J.L.N. has received research funding from the International Rett Syndrome Foundation, the National Institutes of Health and Rett Syndrome Research Trust; and personal consultancy fees from Acadia Pharmaceuticals, Analysis Group, AveXis, GW Pharmaceuticals, Hoffmann-La Roche, Myrtelle, Neurogene, Newron Pharmaceuticals, Signant Health and Taysha Gene Therapies and for the preparation of CME activities for Medscape and PeerView Institute; serves on the scientific advisory board of Alcyone Lifesciences; is a scientific cofounder of LizarBio Therapeutics; and was a member of a data safety monitoring board for clinical trials conducted by Ovid Therapeutics. A.K.P. is coeditor of | PMC10287558 |
References | PMC10287558 | |||
1. Introduction | gastrointestinal symptoms, lactose intolerance [Gastric transit, abdominal pain | Lactose maldigesters report an increase in abdominal pain due to the consumption of milk containing a mixture of A1 and A2 β-casein as compared to milk containing only A2 β-casein. Gastric transit affects gastrointestinal symptoms and rapid transit has been associated with an increase in abdominal pain. We conducted a double-blinded, randomized, crossover trial in 10 lactose maldigesters. Subjects consumed each of the two types of milk: conventional milk containing 75% A1 β-casein and 25% A2 β-casein and A2 milk containing 100% A2 β-casein. Magnetic resonance images were acquired, and abdominal pain was rated and recorded at 0, 10, 30, 60 and 120 min after milk consumption. The volume of milk in the stomach was calculated using FSL software. The volume of milk in the stomach after consuming milk with 75% A1 β-casein and 25% A2 β-casein was significantly lower at 30 (Casein and whey are the two major proteins in cow’s milk. β-casein forms approximately 30% of protein in bovine milk [Several studies have shown that the consumption of milk containing A1 β-casein aggravates symptoms of lactose intolerance [Gastric transit time is associated with gastrointestinal symptoms [We hypothesized that the lower symptom scores for abdominal pain due to consumption of milk containing only A2 β-casein as compared to milk containing A1 and A2 β-casein was related to the difference in the gastric emptying time. | PMC9963893 | |
2. Materials and Methods | PMC9963893 | |||
2.1. Subject Enrolment, Allocation and Inclusion Criteria | RECRUITMENT | This was a randomized, double-blinded, crossover trial. Subjects aged 18–65 years were recruited using flyers, advertisements in local and campus newspapers and email. The recruitment started in March 2021 and the data collection was completed in October 2022. Sixty-one people indicated an interest in the study and contacted the study staff through email or phone ( | PMC9963893 | |
2.2. Exclusion Criteria | HIV, hepatitis B, diabetes mellitus, ulcers, gastrointestinal tract | ADVERSE EVENTS, DIABETES MELLITUS, ULCERS, CONGESTIVE HEART FAILURE, HEPATITIS C, ABNORMAL GASTROINTESTINAL MOTILITY | Subjects were excluded from the study if they met one or more of the following criteria: currently pregnant, abnormal gastrointestinal motility, history of gastrointestinal tract surgery, presence of a medical condition that could confound collection of adverse events, ulcers, diabetes mellitus, congestive heart failure, HIV, hepatitis B, hepatitis C, use of systemic antibiotics thirty days prior to screening; had certain implants, metallic objects or irremovable jewelry on the body that could produce artefacts or potentially harm the subjects during the MRI scan. | PMC9963893 |
2.3. Intervention | Two milks were fed: Conventional milk containing 75% A1 β-casein and 25% A2 β-casein (Kroger | PMC9963893 | ||
2.4. Nutrient Analysis | Total sugar, fat and protein in conventional milk and A2 milk were analyzed by Eurofins Food Integrity and Innovation (Eurofins Food Chemistry Testing US, Inc., Madison WI, USA). A1 and A2 β-casein in the two types of milk were analyzed using mass spectrometry at Purdue Proteomics Facility. | PMC9963893 | ||
2.4.1. Analysis of A1 β-Casein/A2 β-Casein Using Liquid Chromatograph Triple Quadrupole Mass Spectrometer (LC-MS/MS) | SEPARATION, AIDS | One hundred microliters (100 µL) of each milk sample (conventional milk and A2 milk) were denatured using 400 µL of 8 M urea and 10 mM DTT (dithiotheitol), and vortexed for 15 min at room temperature. Denaturation with urea aids in the separation of fat from protein. Fat removal was followed by the process of centrifugation. The proteins extracted from the solution were alkylated with 20 mM IAA (iodoacetamide) and digested with pepsin for one hour at room temperature using a 1:20 enzyme-to-substrate ratio. After digestion, peptides were desalted using C | PMC9963893 | |
2.4.2. Sugar Analysis | The analysis for the sugar profile was conducted using gas chromatography with flame ionization detection [ | PMC9963893 | ||
2.4.3. Protein Analysis | Dumas method, also known as combustion method, was used to analyze protein in milk samples [ | PMC9963893 | ||
2.4.4. Fat Analysis | Base hydrolysis was the method used to determine the fat content in milk samples [ | PMC9963893 | ||
2.5. Study Procedure | abdominal pain | Subjects reported to Purdue MRI Facility for two visits, at least six days apart. Subjects consumed a low-fiber dinner the night before the test feeding, fasted twelve hours prior to their visit and avoided drinking water three hours prior to the visit. On the day of the visit, scans were performed using a Magnetom 3T Prisma MRI scanner (Siemens Healthineers, Erlangen, Germany). Large flex surface coil (18-channel) and spine coil (32-channel) were used to acquire the coverage of the entire abdomen. Coronal abdominal images were acquired with HASTE sequence (repletion time (TR) = 1200 ms; echo time (TE) = 101 ms; flip angle (FA) = 160°; field-of-view (FOV) = 340 × 340 mm; in-plane resolution = 1.3 × 1.3 mm; 45 coronal slices; slice thickness = 3 mm; GRAPPA = 3). The prospective navigator-triggered HASTE sequence took about 4 min. An initial scan was performed to acquire images of the baseline empty stomach. Subjects then consumed a milk dose, and the amount of milk was calculated in ml using the following formula:One cup of milk, or 245 mL, contains approximately 11 g of lactose. Subjects consumed 0.5 g of lactose per kg body weight. The amount of milk (mL) and lactose (g) consumed by subjects were the same during the two MRI visits. Coronal MRI images were acquired at 10, 30, 60 and 120 min with HASTE sequence after the consumption of milk. Subjects also rated and recorded their abdominal pain at 0, 30, 60, 90 and 120 min using a six-point Likert scale. The scale ranged from 0 to 5, where 0 indicated no symptom, 1 was for slight abdominal pain, 2 for mild, 3 for moderate, 4 for moderately severe and 5 for severe abdominal pain. | PMC9963893 | |
2.6. Study Ethics | The study protocol (ClinicalTrials.gov #NCT05658861) was reviewed and approved by the Purdue University Institutional Review Board (#IRB-2019-296). The study complied with the Helsinki Declaration of 1975 as revised in 2008 [ | PMC9963893 | ||
2.7. Image Analysis | A software tool within FMRIB’s Software Library (FSL v5.0.11) [ | PMC9963893 | ||
2.8. Statistical Analysis | USA).The, USA).Conventional milk, abdominal pain | The volume of both kinds of milk in the stomach during the two-hour study was compared using two-way repeated measures ANOVA. The normality of the data was tested using Shapiro–Wilk. Log transformation was used to bring the data into a normal distribution. This analysis was conducted using RStudio (v2022.07.2+576.pro12 Spotted Wakerobin, Posit, Boston, MA, USA).The statistical difference between the volume of conventional and A2 milk at each time point was analyzed with the paired Wilcoxon signed-rank test was used to compare the symptom scores. A non-parametric test was used since the symptom scores were ordinal data rated using a Likert scale and they were not normally distributed. The analysis for abdominal pain was conducted using Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, Version 28.0; IBM Corp., Armonk, NY, USA).Conventional milk was compared with A2 milk by measuring the volume of milk at different time points for gastric transit and with symptom scores for abdominal pain. The volume of milk was converted from millimeter cubed (mm | PMC9963893 | |
3. Results | PMC9963893 | |||
3.1. Baseline Characteristics | maldigestion | Five out of the twenty-three subjects who were phone screened were ineligible to continue in the study due to their current medical condition, lack of milk avoidance and/or presence of metallic implants near the region of the scan. The remaining eighteen were eligible to be assessed for maldigestion with a hydrogen breath test; however, only fifteen subjects responded to attempts to schedule the screening test. Ten out of the fifteen subjects produced a 20 ppm rise in hydrogen during the six-hour milk challenge, indicating maldigestion. These ten subjects completed the two milk-feeding interventions (Seven female subjects and three male subjects of an age range between 19 and 42 and an average BMI of 23 kg/m | PMC9963893 | |
3.2. Nutrient Analysis | The nutrient compositions of the A2 milk and conventional milk are shown in | PMC9963893 | ||
3.3. Gastric Emptying and Transit Volume | The average volume of conventional milk in the stomach over the two-hour period was significantly lower than the average volume of A2 milk ( | PMC9963893 | ||
3.4. Abdominal Pain | abdominal pain | The total symptom score for abdominal pain reported by all maldigesters was 20 for conventional milk and 12 for A2 milk. This difference was not statistically significant ( | PMC9963893 | |
3.5. Adverse Events | ADVERSE EVENTS | There were no adverse events reported by subjects during the study. | PMC9963893 | |
4. Discussion | milk, New-World milk, lactose intolerance, gastrointestinal and colonic transit | LACTOSE INTOLERANCE | No previously reported studies have compared the gastric emptying time of milk containing A1 and A2 β-casein with milk containing only A2 β-casein. Therefore, this pilot study could be used for power calculations for larger-scale studies. We planned to recruit 10 subjects to examine a difference in transit. We completed the trial after we collected data from all 10 participants. While the sample size is modest, the differences in gastric transit are highly significant and biologically relevant. We suggest that the gastric transit of New-World milk containing both A1 and A2 β-casein is more rapid as compared to Old-World milk containing only A2 β-casein. Jianqin et. al. reported a slower total gastrointestinal and colonic transit of milk containing A1 β-casein in comparison to A2 milk [Slow gastric emptying is associated with better tolerance and digestion among maldigesters [We did not stratify subjects based on age, gender or race because evidence suggests that lactose intolerance does not depend on demographics but on the dose and differences in the lactase non-persistent gene [The nutrient composition of conventional milk and A2 milk were very similar. The slight difference in fat could account for some of the difference in transit [ | PMC9963893 |
5. Conclusions | maldigestion, abdominal pain | In summary, the gastric transit of milk containing both A1 and A2 β-casein was faster as compared to milk containing only A2 β-casein. The abdominal pain resulting from New-World milk and A2 milk was not different, likely due to the small sample size. The transit findings reported here could be the reason for less maldigestion following the consumption of milk containing only A2 β-casein as compared to milk containing both A1 and A2 β-casein in lactose maldigesters [ | PMC9963893 | |
Author Contributions | Conceptualization, D.A.S. and M.R.; methodology, M.R., X.Z., U.D. and D.A.S.; formal analysis, M.R. and X.Z.; writing—original draft preparation, M.R.; writing—review and editing, M.R. and D.A.S. All authors have read and agreed to the published version of the manuscript. | PMC9963893 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Purdue University (protocol IRB-2019-296 approved on 02 September 2021). | PMC9963893 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9963893 | ||
Data Availability Statement | The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions. | PMC9963893 | ||
Conflicts of Interest | The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. | PMC9963893 | ||
Appendix A | PMC9963893 | |||
Inclusion and Exclusion Criteria for Phone Screening | mellitus, IBS, Crohn’s disease, UC, amyloidosis, abnormal gastrointestinal motility, chronic constipation, aneurysm, uremia, gastrointestinal bypass, alcoholism, ulcerative colitis, SIBO, diverticulosis, epilepsy/seizure, prostate radiation, gastroparesis, Hepatitis, Hepatitis B, cardiac defibrillator, IBD, GERD, Parkinson’s disease, malnutrition, claustrophobia | INFLAMMATORY BOWEL DISEASE, GERD, ULCERS, AMYLOIDOSIS, NEUROMUSCULAR DISEASES, CELIAC DISEASE, ANEURYSM, UREMIA, GASTRO-ESOPHAGEAL REFLUX DISEASE, DISORDERS, BILIARY DISEASE, CHRONIC PANCREATITIS, ABNORMAL GASTROINTESTINAL MOTILITY, CONGESTIVE HEART FAILURE, ULCERATIVE COLITIS, BACTERIAL OVERGROWTH SYNDROME, DIVERTICULOSIS, AIDS, IMMUNODEFICIENCY, GASTROPARESIS, HEPATITIS, HEPATITIS B, IRRITABLE BOWEL SYNDROME, COLLAGEN VASCULAR DISEASES, PANCREATIC INSUFFICIENCY, MALNUTRITION | Inclusion Criteria:Ability/desire to provide informed consentAged 18 to 65 years inclusive at screeningMilk intolerant and identified as a lactose maldigester while participating in the Milk Protein Study (applicable only for subjects from the previous milk protein study and not applicable for new subjects)Current or recent history of intolerance to or avoidance of dairy of at least one month duration (by self-report and self-reported symptoms)Willing to return for all study visits and complete all study related proceduresAble to understand and provide written informed consent in EnglishExclusion Criteria:Currently pregnantDiagnosed with any of the following disorders known to be associated with abnormal gastrointestinal motility such as gastroparesis, amyloidosis, neuromuscular diseases (including Parkinson’s disease), collagen vascular diseases, alcoholism, uremia, malnutrition or untreated hypothyroidismHistory of surgery that alters the normal function of the gastrointestinal tract including, but not limited to, gastrointestinal bypass surgery, bariatric surgery, gastric banding, vagotomy, fundoplication or pyloroplasty [Note: history of uncomplicated abdominal surgeries such as removal of an appendix more than 12 months prior to screening will not be excluded]Past or present: Organ transplant, chronic pancreatitis, pancreatic insufficiency, symptomatic biliary disease, Celiac disease, chronic constipation, diverticulosis, inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn’s disease (CD), small intestine bacterial overgrowth syndrome (SIBO), gastroparesis, gastro-esophageal reflux disease (GERD), Irritable Bowel Syndrome (IBS) or any other medical condition with symptoms that could confound collection of adverse eventsActive ulcers or history of severe ulcersDiabetes mellitus (type 1 and type 2)Congestive Heart Failure (CHF)Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis CRecent use of systemic antibiotics, defined as use within 30 days prior to screeningAny of the following: Worked with metal (grinding, fabrication, etc.) or had an injury to the eye involving a metallic object, e.g., metallic slivers, foreign body, been injured by a metallic object that may NOT have been completely removed (e.g., bullets, shrapnel, BBs), had a reaction to a contrast medium used for MRI or CT, have claustrophobia (fear of closed places), been diagnosed with epilepsy/seizure, any reason for being unable to remain still for long periods of time, cardiac pacemaker, any type of prosthesis (eye, penile), implanted cardiac defibrillator, heart valve prosthesis/stents, aneurysm clip, shunt (spinal/intraventricular), neuro or bone stimulator, wire sutures or surgical staples, insulin or infusion pump, bone/joint pin, screw, nail, plate, implanted drug infusion device, body tattoos, cochlear, otologic or ear implant, tattooed makeup (eyeliner, lip, etc.), prostate radiation seeds, breast tissue expander, IUD (intrauterine device), hearing aids, transdermal medicine patch (Nitro), body piercing(s), any metallic implants or objects or any other reason the participant thinks they would not be a good candidate for MRIAny other conditions/issues noted by the study staff and/or principal investigator that would impact participation and/or protocol compliance | PMC9963893 |
References | abdominal pain | Study flow. HBT, hydrogen breath test; MRI, magnetic resonance imaging analysis.Image analysis using FMRIB’s Software Library (FSL v5.0.11). (Image analysis using FMRIB’s Software Library (FSL v5.0.11). (The volume of A2 milk in the stomach was significantly lower at 30, 60 and 120 min as compared to the volume of conventional milk in the stomach: * Magnetic resonance images showing the gastric volume of conventional milk and A2 milk and volume calculated in milliliters (mL) at 10, 30, 60 and 120 min.No effect or difference was detected in abdominal pain between A2 milk and conventional milk (Baseline and demographic characteristics of lactose maldigesters enrolled in the trial.Nutrient composition of the two milk treatments. | PMC9963893 | |
Objective | ORAL MUCOSITIS, ACUTE LEUKEMIA | This study aimed to investigate the clinical effects of recombinant human interleukin-11 (rhIL-11) gargle on preventing and treating oral mucositis (OM) after chemotherapy for acute leukemia. | PMC10337102 | |
Methods | mucositis, pain | MUCOSITIS, ORAL MUCOSITIS, ACUTE LEUKEMIA | This single-site, prospective, observer-blinded, nonrandomized controlled trial was conducted on 74 patients with acute leukemia, who were divided into the experimental and control groups. The patients in the experimental group were treated with IL-11 gargle, and those in the control group were treated with sodium bicarbonate gargle. We examined the time and severity of oral mucositis, severity and duration of associated pain, healing time of mucositis, effects of OM on eating, and levels of T-cell subset indicators before and after treatment to evaluate the effects of IL-11 treatment. | PMC10337102 |
Results | pain, ulcer, Mucositis | ULCER, MUCOSITIS | The proportion of patients with severe OM was significantly lower in the experimental group than in the control group. Mucositis occurred later in the experimental group compared with the control group. The degree and duration of pain, ulcer healing time, and effects on eating were lower in the experimental group compared with the control group. Following treatment, the levels of all T-cell subset indicators improved in each of the two groups. However, the rate of improvement was significantly higher in the experimental group than in the control group. These differences were statistically significant ( | PMC10337102 |
Conclusions | pain | ACUTE LEUKEMIA | IL-11 gargle reduced the severity of OM after chemotherapy for acute leukemia. Treatment with IL-11 relieved pain, promoted healing, and improved the curative effect of the condition, making it worthy of clinical promotion. | PMC10337102 |
Keywords | PMC10337102 | |||
Introduction | cancer of the hematopoietic system, leukemia, erythema, ulcers, malignant tumors, systemic infection, acute leukemia | ORAL MUCOSITIS, LEUKEMIA, DISEASE, ERYTHEMA, ULCERS, COMPLICATION, MALIGNANT TUMORS, SYSTEMIC INFECTION, BONE MARROW SUPPRESSION, ACUTE LEUKEMIA, ACUTE LEUKEMIA | Oral mucositis (OM) is an inflammatory reaction of epithelial tissue that involves symptoms such as oral mucosal erythema and ulcers. The main antitumor treatments that cause OM include chemotherapy, radiotherapy, molecular targeted therapy, and hematopoietic stem cell transplantation for malignant tumors [Acute leukemia is a cancer of the hematopoietic system. At present, chemotherapy remains the primary treatment method for the disease. However, acute leukemia chemotherapy and the drugs used for treatment can result in bone marrow suppression, low immunity, and systemic infection in severe cases. In turn, this has caused OM to become the main nonhematological complication of leukemia [ | PMC10337102 |
Patients and methods | PMC10337102 | |||
Patients | PMC10337102 | |||
Patient demographics | AML, acute leukemia | ACUTE MYELOID LEUKEMIA, ADULT AML, AML, SECONDARY, ACUTE LEUKEMIA | This study involved 74 patients with acute leukemia (including secondary and transformed) admitted to our hospital from June 2021 to June 2022. This group consisted of 59 patients with acute myeloid leukemia (AML), who all met the diagnostic criteria for adult AML from the Chinese Medical Association [ | PMC10337102 |
Inclusion criteria | AML, ALL | AML, ACUTE LEUKEMIA | Patients were included in this study if they (1) had AML or ALL diagnosed by bone marrow aspiration and flow immunophenotyping and receiving the first course of induction chemotherapy; (2) were diagnosed with acute leukemia, after complete response (CR), and receiving a course of consolidation and intensive chemotherapy; and (3) could take care of themselves, with good dental and periodontal cleanliness, and had good treatment compliance. During treatment, they followed daily oral care and were guided by dental doctors. | PMC10337102 |
Exclusion criteria | ORAL ULCERS, PERIODONTAL DISEASES, MALIGNANT TUMORS, OTHER INFECTIOUS DISEASES, DISEASES | Patients were excluded from this study if they (1) had active periodontal diseases that required treatment and refractory oral ulcers prior to this study; (2) were pregnant and lactating; (3) presented with other malignant tumors; (4) had other infectious diseases; or (5) had severe heart, brain, lung, liver, kidney, or other diseases that prevented them from tolerating chemotherapy. | PMC10337102 | |
Methods | PMC10337102 | |||
Chemotherapy regimens | ALL | AML | Each patient in this study was treated with a reasonable chemotherapy regimen based on their own conditions. Drugs commonly used to treat AML include idarubicin, cytarabine, high-spinel, etoposide, fludarabine, cladribine, azacitidine, decitabine, arsenic acid, venetoclax, and other novel chemotherapy drugs. Drugs commonly used to treat ALL include cyclophosphamide, vincristine, pirarubicin, methotrexate, cytarabine, dexamethasone, pegaspargase, etoposide, tyrosine kinase inhibitors imatinib, dasatinib, and other novel chemotherapy drugs. The choice of chemotherapy drugs was standardized for patients within each group, implying that these patients were not treated significantly differently. | PMC10337102 |
OM treatment | bone marrow suppression | MUCOSAL ULCERS, REMISSION, DETACHMENT, BONE MARROW SUPPRESSION | As part of the intervention, the patients in the experimental group gargled with IL-11 rinse, which was formulated as follows: 3 mg of IL-11 was added to 100 mL of normal saline, which was then stored at 2–8 °C and dispensed every day. The patients in the control group gargled with a solution of 5% sodium bicarbonate and purified water at a ratio of 1:1. The patients in both groups gargled with their respective solution in the morning, after lunch, after dinner, and half an hour before going to bed for 4 days. Each time, they rinsed with water before gargling and gargled with about 25 mL of solution for 5 min. The intervention began on day 1 of chemotherapy and ended after bone marrow suppression phase remission (detachment of granulocyte deficiency) or after their oral mucosal ulcers had healed. | PMC10337102 |
Observation indicators | agranulocytosis, erosion, pain | DISEASE, EROSION, DISEASES, GRANULOCYTOSIS | The main observation indicators used in this study were as follows: (1) the severity of OM and its timing relative to the first day of chemotherapy; (2) the severity of the pain caused by OM and the duration from the onset of pain to its relief; (3) the time from the inception of OM to its healing; (4) the influence of OM on eating, where patients with reduced food consumption, liquid food intake, or an inability to eat due to OM erosion or pain were considered to have an impact on eating and the rest were not; and (5) T-cell subsets of patients detected at the start of agranulocytosis or OM. As with the other indicators examined before treatment, T-cell subsets were re-examined after oral gargle treatment, and the differences between the two groups were compared.According to the World Health Organization (WHO) [Physicians with experience in the treatment of oral diseases evaluated the severity of OM and degree of pain. Unaware of the disease groupings, the same physician assessed the entire observational study process. | PMC10337102 |
Statistical analysis | SPSS 20.0 software was used to perform all statistical analyses. The continuous data were expressed as mean ± standard deviation (x ± s) and compared using the | PMC10337102 | ||
Results | PMC10337102 | |||
Patient characteristics | The 74 patients were divided between the experimental and control groups, with 37 patients in each group. Patient inclusion, exclusion, and follow-up are shown in Fig.
Patients inclusion, exclusion, and follow-up
Comparison of baseline clinical data between the observation and control groups | PMC10337102 | ||
Severity and timing of OM | More patients in the experimental group had OM of grade 0 and grade I, whereas more patients in the control group had OM of grade II and above (
OM stage and timing after chemotherapy | PMC10337102 | ||
Level and duration of OM pain | pain | The patients in the experimental group mostly experienced painlessness or mild symptoms of pain, whereas the patients in the control group had significantly higher levels of moderate and severe pain (
Level and duration of OM pain | PMC10337102 | |
Effects of OM on eating and mucosal healing time | The onset of OM had a significantly higher impact on eating in the control group compared with the experimental group (
OM effects on eating and healing time | PMC10337102 | ||
T-cell subset detection before and after treatment | Prior to treatment, the CD3+, CD4+, CD8+, and CD4+/CD8 + levels did not significantly differ between the two groups. The levels of each of these indicators increased as a result of IL-11 treatment, where the rate of increase in the experimental group was significantly higher than that in the control group (
T-cell subset detection before and after treatment (%) | PMC10337102 | ||
Discussion | pulpitis, swelling, inflammation, edema, periodontitis, infections, pain, infection, active periodontal diseases, friction, mucositis, ALL, Acute leukemia, acute leukemia | PERIODONTAL DISEASE, PULPITIS, ACUTE LEUKEMIA, PERIAPICAL PERIODONTITIS, INFLAMMATORY RESPONSES, INFLAMMATION, EDEMA, INFECTIONS, REMISSION, MUCOSITIS, DISEASES, ACUTE LEUKEMIA, PERIODONTITIS, INFECTION, COMPLICATIONS, INFILTRATE, DISEASE, MALNUTRITION, MUCOSAL INFLAMMATION | Acute leukemia is a malignant clonal disease involving hematopoietic stem cells. Abnormal primitive cells proliferate and extensively infiltrate the bone marrow to inhibit normal hematopoiesis. At present, combined chemotherapy remains the primary form of treatment for acute leukemia. Acute leukemia commonly causes OM due to the characteristics of the disease itself and the influence of chemotherapy drugs [OM causes local redness, swelling and pain, difficulty chewing, and issues with the patient’s normal eating. If left untreated for a long time, these symptoms can lead to malnutrition, further weakening the patient’s resistance, exacerbating infections, intensifying pain, prolonging treatment time, and imposing a greater financial burden on the patient [IL-11 is an anti-inflammatory factor in the interleukin family. IL-11 not only stimulates the differentiation and maturation of hematopoietic progenitor cells (megakaryocytes, granulocytes, and erythroid cells) but also counteracts and regulates the inflammatory cytokines produced by infection and damage caused by inflammation through a negative feedback regulation mechanism. At the same time, IL-11 acts on epithelial cells, maintains metabolism and homeostasis, and protects and strengthens the mucosal epithelium, thereby reducing edema and inhibiting inflammatory responses [In this study, patients with acute leukemia who were treated with chemotherapy were selected as research subjects to observe the occurrence time, severity, pain, degree, duration, mucosal healing time, and effects of OM after topical treatment with IL-11 gargle on eating. Our results showed that IL-11 treatment could not completely prevent the occurrence of OM, but did reduce the incidence and grade of the condition. Furthermore, IL-11 treatment lowered pain caused by OM, reduced its impact on eating, and promoted mucosal recovery. Preventing OM complications not only relieved patients of potential pain but also ensured the intensity and efficacy of chemotherapy, thus improving the prognosis of acute leukemia. Overall, we concluded that IL-11 was effective in treating OM. However, further research is needed on the mechanism of IL-11 in treating mucositis. More specifically, future research should use subgroup analysis to better understand how IL-11 reduces the effects of cytokines and promotes the repair of mucosal epithelial cells.Periodontal diseases such as pulpitis, periapical periodontitis, and periodontitis that already exist in patients before chemotherapy can also impact the occurrence and development of oral mucosal inflammation. We excluded patients with active periodontal diseases that required treatment before the study and tried to exclude the impact of this factor on the results. In this study, 11 elderly patients used dentures, including 6 in the IL-11 group and 5 in the control group. The friction and movement of dentures might cause oral mucosal inflammation and worsen oral mucosal inflammation, but no difference was found between the two groups and the analysis of later results was not affected.Cell subsets, including CD3+, CD4+, and CD8 + cells, are important indicators for evaluating the immune function of the body. All T cells are positive for CD3 and further divided into CD4+, CD8+, and regulatory T cells based on their respective function. CD4 + cells mediate cellular immune responses and assist humoral immune responses. The main function of CD8 + cells is to kill target cells specifically and directly. CD4 + and CD8 + cells are in a constant state of balance and play an essential role in maintaining normal immune function. A decrease in the ratio of CD4 + to CD8 + cells indicates that the immune function of the body is in an imbalanced state, which may easily lead to various diseases including OM [OM treatment excludes the application of anti-infection and biological factors, and includes other drug and nondrug therapies. For example, most of the patients with ALL had OM of grade III or above during the high-dose methotrexate course in this trial. The treatment for these patients included not only IL-11 but also local and systemic administration of leucovorin to reduce the damage caused by chemotherapy and speed up mucosal healing. In addition, various oral mucosa protective agents, oral care solutions, traditional Chinese medicine preparations, honey adjuvants, and other natural medicines can be used to improve the discomfort caused by OM, effectively reducing the incidence of mucositis and improving its remission rate [The findings indicate that the incidence and severity of OM are affected by different chemotherapy or radiotherapy protocols [This study had several limitations. First, it was a single-site, prospective, observer-blinded, nonrandomized controlled trial. It had small sample size and included patients who received treatment in our hospital, leading to bias in the analysis results. We need to further expand the sample size in future studies to increase the credibility of the findings. Second, the single application of IL-11 in treating oral mucosal inflammation had limited efficacy, and the combined effects of other drugs and nondrug treatments were not addressed in this study. Finally, the mechanism of IL-11 in treating oral mucosal inflammation needs further basic experimental research.In summary, a precise prevention plan should be formulated according to risk stratification for treating OM after chemotherapy for acute leukemia. Besides IL-11 gargle, individualized prevention and treatment regimens for OM should incorporate other drugs and nonpharmaceutical measures. We may better relieve suffering and improve quality of life by providing personalized treatment plans according to the characteristics of the patient. | PMC10337102 |
Acknowledgements | None. | PMC10337102 | ||
Authors’ contributions | YL Z, YX L and XR M carried out the studies, participated in collecting data, and drafted the manuscript. J W, PY Z, AL H and B L performed the statistical analysis and participated in its design. Z H, L Z and W Z participated in acquisition, analysis, or interpretation of data and draft the manuscript. All authors read and approved the final manuscript. | PMC10337102 | ||
Funding | None. | PMC10337102 | ||
Data availability | All data generated or analysed during this study are included in this published article. | PMC10337102 | ||
Declarations | PMC10337102 | |||
Ethics approval and consent to participate | All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. This study was approved by the Ethics Committee of the Second Affiliated Hospital of Xi’an Jiaotong University. All patients provided written informed consent prior to treatment. The study was carried out in accordance with the applicable guidelines and regulations. | PMC10337102 | ||
Consent for publication | Not applicable. | PMC10337102 | ||
Competing interest | The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | PMC10337102 | ||
References | PMC10337102 | |||
Background | death, hypertension, cardiovascular disease | EVENTS, HYPERTENSION, CARDIOVASCULAR DISEASE | Early identification and control of hypertension is critical to reducing cardiovascular disease events and death. U.S. Preventive Services Task Force guidelines recommend health care professionals screen all adults for hypertension, yet 1 in 4 adults with hypertension are unaware of their condition. This gap between guidelines and clinical practices highlights an important opportunity to improve blood pressure (BP) screening and hypertension diagnosis, including measurement outside of clinic settings. To identify targets for future diagnostic interventions, we sought to understand primary care physicians' (PCPs) beliefs and practices regarding use of common forms of BP measurement. | PMC9874175 |
Methods | Study participants were PCPs ( | PMC9874175 | ||
Results | HYPERTENSION | Overall, PCPs preferred and trusted clinic BP measurement for diagnosing hypertension, particularly when measured with a manual sphygmomanometer. Concerns with HBPM included the belief that patients did not follow protocols for rest and body positioning at home, that home machines were not accurate, that home BPs could not be entered into the medical record, and that HBPM would make some patients anxious. Issues regarding kiosk measurement included beliefs that the public setting created stress for patients, that patients did not follow resting protocols when using kiosks, and concerns about the maintenance of these machines. ABPM was recognized as highly accurate but was not perceived as accessible. Additionally, some PCPs found it challenging to interpret the multiple readings generated by ABPM and HBPM, especially when these readings differed from clinic BPs. | PMC9874175 | |
Conclusions | HYPERTENSION | Our findings suggest that both additional physician education and training and investments in equipment and system-level processes are needed to increase the acceptance and utilization of out of office BP measurement for identification and treatment of hypertension. These changes are needed to improve ensure everyone in the U.S receive optimal care for hypertension. | PMC9874175 | |
Trial registration | ClinicalTrials.gov | PMC9874175 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12875-022-01950-1. | PMC9874175 | ||
Keywords | PMC9874175 | |||
Introduction | disability, death, hypertension, Hypertension | HYPERTENSION, HYPERTENSION | Hypertension is the most common cause of avoidable death and disability globally [Currently, the U.S. Preventive Services Task Force (USPSTF) guidelines recommend screening all adults aged 18 years or older for hypertension (an “A” recommendation, strong evidence of benefit) [These guidelines contrast with current practice for many primary care physicians (PCPs) who rely almost exclusively on clinic-based BP measurement using manual or automated sphygmomanometers and no averaging of readings [The literature on health care professionals’ knowledge and attitudes regarding BP measurement, especially when used for diagnosis or taken outside of a clinic, is limited. Even fewer studies focus on knowledge and beliefs of health care professionals in the U.S., which has systemic constraints on out-of-clinic BP measurement [This qualitative study interviewed physicians whose patients participated in the BP-CHECK study about their beliefs and practices related to using different BP measurement methods and their experience with using HBPM and ABPM for diagnosing hypertension. Our aim was to shed light on barriers and potential facilitators for improving hypertension diagnosis. | PMC9874175 |
Methods | PMC9874175 | |||
Goal | hypertension | HYPERTENSION | The goal was to assess primary care physicians’ (PCPs) attitudes and practices after being exposed to a variety of BP measurement options for hypertension diagnosis. (See | PMC9874175 |
Sampling and recruitment | RECRUITMENT | This qualitative study included PCPs (Summary of BP-CHECK measurement methodsThe interviews analyzed for this paper focused on PCPs at Kaiser Permanente Washington who received ABPM results for a BP-CHECK study participant, to ensure they had some experience with this testing methodology. A purposive sampling matrix was used to prioritize recruitment of PCPs who received 2 or more ABPM patient reports with the goal of approximately 75% of participating PCPs receiving 2 or more ABPM reports. Invitations to participate and study information summaries were sent to PCPs via email, followed by at least 3 attempts at phone outreach if there was no response. | PMC9874175 | |
Data collection | SE | Phone interviews took place between March 2018 and April 2019 and were conducted by experienced qualitative researchers (SE and LH) who followed a semi-structured interview guide. Participants provided verbal consent and were offered $50 as thanks for participation. Interviews were recorded and transcribed for analysis. | PMC9874175 | |
Data analysis | SE | Transcripts were coded by three qualitative researchers (SE, LH & CH). Using a template analysis approach [Once coding was complete, data were pulled by code and selected codes were analyzed further. This analysis was summarized in one or more analytic coding memos [ | PMC9874175 | |
Discussion | arrhythmias, hypertension, anxiety | ARRHYTHMIAS, HYPERTENSION, PCP, HBP | Interviews with PCPs who had experience with ABPM through the BP-CHECK randomized trial revealed that overall, they preferred clinic-based BP measurement for hypertension diagnosis, especially manual BP measurement. PCPs viewed measurement in clinics as accurate because it is performed by a trained professional who can ensure optimal patient rest and body positioning. For HBPM, PCPs worried about patients’ ability to follow best practices regarding rest and body positioning, the accuracy of the monitors they have at home, and whether repeated measurements would cause patient anxiety. These results suggest that PCPs’ confidence in clinic-based BPs and concerns about HBP may be misplaced given that the main findings of the BP-CHECK study found HBPM for diagnostic testing was more accurate than clinic-based BP follow-up measurements. However, in the BP-CHECK study, patients received free validated home BP monitors and were trained to use them [PCPs were also concerned that there was no acceptable way to document HBPM readings in the EHR for HEDIS purposes at the time of the interviews. (HEDIS rules have since changed to allow quality measurements to include manual and electronic entry of BP measurements taken at home.) Also, subsequent to the COVID-19 pandemic, the Center for Medicare and Medicaid Services approved use of home BP measurements for reporting quality metrics. Pursuant to this change, our health care system is testing several strategies for collecting BPs from home, including a BP telemonitoring program with BP measurements directly transferred to the EHR or patients hand-entering their home BP readings into secure email sent via the patient's shared EHR.For kiosk-based measurements, PCPs were concerned about maintenance of the BP machines, whether testing in a public setting created stress, and patients’ ability to follow recommended resting time and positioning prior to taking measurements. PCPs also noted that kiosk results tended to be high, which aligns with the results of the main study that found kiosks but not clinic or HBPM methods tended to give higher readings than ABPM [While interviewees acknowledged that ABPM is a very accurate method for measuring BP for diagnostic purposes, they correctly perceived that it was not readily available. ABPM devices are expensive and require specialized software and staff who are trained to do ABPM testing and retrieve the data. However, ABPM could be made more easily available, similar to devices that track arrhythmias that can be set up within primary clinics or mailed to patients directly. We know of only one study that is testing strategies for improving access to ABPM and home BP hypertension diagnostic testing and the results are not yet available [Our findings are consistent with and expand on prior studies that explored PCP beliefs and preferences about out-of-clinic BP measurement. One key finding from the literature comes from a systematic review of qualitative studies on patients and physicians. The studies were conducted in the U.K. (6 studies), Sweden (1), Malaysia (1), Canada (1) and the U.S. (2) and were about self-measurement of BP for management of hypertension. For hypertension management (not diagnosis), the review found that physicians: 1) recognized that that home monitoring often gave lower measurements than clinic and that created a dilemma about which BP measurements to use, 2) were concerned that HBPM would increase anxiety for patients, and 3) reported that variability in BP introduced by HBPM increased treatment uncertainty. A survey of general practitioners in the U.K. found that only a minority recognized that threshold values for diagnosis using HBPM were lower than those for clinic measurement [Our study also has a unique focus on diagnosis rather than management: Diagnosis has important implications for if and how individuals understand and begin management for their hypertension. Our findings reinforce Fletcher et al.’s themes regarding the concerns that PCPs have with self-monitored BP, including difficulties interpreting variable BP readings and reconciling them against clinic measurements as well as perhaps unfounded worries that HBPM causes patients to become overly anxious about their BP [Our findings provide additional insight into the reliance and trust that PCPs place in clinic BP measure. PCPs in these interviews articulated a preference for in clinic BP measurement for diagnosis, which was reinforced by a parallel survey our team conducted that found that 64.7% of PCPs and 88.9% of registered nurses and MAs endorsed clinic BP as the most accurate measurement method [Our study has many implications for practice. First, our findings highlight the need for education of both PCPs and patients about how to interpret BP values obtained by different methods using established threshold values for abnormal BP that are available for each BP measurement method. Our findings also show the importance for PCPs and patients of understanding the variability in BP and therefore the benefits of multiple readings. Indeed, PCPs appeared to lack understanding about what to do with variable readings and desire to treat BP as a more static vital sign. Our findings also show the need to find ways to demonstrate the accuracy of HBPM and increase PCP confidence in this measurement method. In addition to the need to address PCP knowledge and attitudes toward BP measurement and diagnosis, our results also show the need to address systems barriers for use of HBPM and ABPM, for example by finding secure, user-friendly mechanisms to integrate HBPM results into EHRs, ensuring that these results are acceptable for HEDIS or other quality metrics, and making ABPM more readily available to PCPs. Another policy and systems challenge that health care delivery is facing in the U.S. is that clinics and health plans are not allowed to provide patients with free home BP monitors, because they are considered to be inducements, and would violate anti-kickback laws. They can, however, loan patients home BP monitors, but getting the monitors back and cleaning them for the next patients presents additional barriers. Resources for training patients to use home BP monitors properly also might not be easily available. Overall, both increased education for PCPs regarding how best to screen for and diagnose hypertension in primary care settings and changes to clinical workflow and infrastructure are needed to improve the rate of hypertension diagnosis and treatment in the U.S.Limitations to our study include that it was conducted in a single large, integrated healthcare system with diverse practice patterns, patients, and providers from 12 clinics. Also, the sample size,while considered robust for qualitative methods, may not have captured all possible PCP perspectives. The PCPs who participated in our study were all physicians and their results may not represent the attitudes and practice patterns of non-physicians who provide primary care within our healthcare system. As part of the study, all interviewees ere offered an educational session on BP measurement and diagnosis conducted by the study leader and had more exposure to ABPM than other PCPs not involved in the trial. We expect that PCPs who were most innovative and interested in research would volunteer to participate in the interviews; therefore, we believe this selection bias may skew our results toward PCPs who are more open to considering new methods for measuring BP and diagnosing hypertension. Finally, the results regarding patient centeredness come from the PCPs rather than patients. Our patient data will be reported in a separate manuscript. | PMC9874175 |
Conclusion | hypertension | EVENTS, HYPERTENSION, PCP | Ensuring that individuals with hypertension are appropriately identified and treated is critical to preventing cardiovascular events. Current guidelines recommend confirming elevated clinic measurements in individuals without known hypertension through out-of-clinic BP measurements to establish a diagnosis. Our findings reveal a need to improve PCP attitudes and practices regarding BP measurement for hypertension diagnosis, especially in light of recent evidence that HBPM is a more sensitive method for detecting hypertension than clinic-based measurement and now that out-of-clinic techniques are recommended for accurate diagnosis. At the same time, health systems need to invest in equipment and systems to measure and integrate out-of-clinic BP measurements into the EHR, to better facilitate the diagnosis and management of hypertension. | PMC9874175 |
Acknowledgements | We would like to thank participating PCPs for their willingness to share their views and experiences, Chris Tachibana for her contributions as the scientific editor on this manuscript, and James Licitra for his help with formatting and references. | PMC9874175 | ||
Authors’ contributions | CH: Led the design of data collection processes. Led the analysis of the data. Led the drafting and revision of the manuscript. LH: Participated in the collection of qualitative data. Assisted with data analysis. Reviewed and gave input on drafts of the manuscript. KE: Participated in the design and execution of the data collection processes, reviewed, and gave input on drafts of manuscript. SM: Participated in data analysis, reviewed, and gave input on interview guides and drafts of manuscript. MA: Participated in the design and execution of the data collection processes, reviewed, and gave input on drafts of manuscript. KM: Participated in the design of the data collection processes, reviewed, and gave input on drafts of manuscript. JM: Participated in the design of the data collection processes, reviewed, and gave input on drafts of manuscript. YH: Participated in the design of the data collection processes, reviewed, and gave input on drafts of manuscript. MT: Participated in the design of the data collection processes, reviewed, and gave input on drafts of manuscript. DJ: Participated in the design of the data collection processes, reviewed, and gave input on drafts of manuscript. BG: As the principal investigator, was responsible for the overall design, collection, and interpretation of the data. Reviewed and gave substantive input into multiple drafts of the manuscript. The author(s) read and approved the final manuscript. | PMC9874175 | ||
Funding | This work was supported through a Patient-Centered Outcomes Research Institute (PCORI) Project Program Award (CER-1511–32979). All statements in this report, including its findings and conclusions, are solely those of the authors and do not necessarily represent the views of PCORI. | PMC9874175 | ||
Availability of data and materials | The authors declare that the data supporting the findings of this study are available within the article. However, additional data are available upon request from the corresponding author [CH]. The data are not publicly available since they contain information that could compromise research respondents’ confidentially that was promised in the consent process. | PMC9874175 | ||
Declarations | PMC9874175 |
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