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Socio-demographic characteristics by site of participants screened for SiVET studies in Kenya and Uganda (2014–2017). | SECONDARY | Entebbe had the biggest proportion of participants aged ≥30 years (49.9%, n = 501) and those with secondary education or higher (49.9%, n = 692). Informal high-risk jobs were reported by 76.4% of participants and Entebbe was the only site with participants having formal jobs (7.9%) as their main occupation. Details in | PMC10351693 | |
Hepatitis B status of participants screened for the SiVET studies in Kenya and Uganda by baseline characteristics. | acute infection, chronic infection, HBV infection | ACUTE INFECTION, CHRONIC INFECTION, NAIROBI | *HR = High Risk; LR = Low RiskThe prevalence of HBV infection was 3.9% among males and 2.8% among females while prevalence by site was: Entebbe (4.9%); Kampala (4.1%) and Nairobi (0.3%). The highest HBV prevalence was found among participants aged 25-29-years (5.2%), those with primary level education (4.5%), and those in informal low risk employment (6.5%). The proportion with chronic infection was higher than that with acute infection in all age groups i.e., <25 years (1.2% vs 0.5%); 25–29 years (5.0% vs 0.5%) and ≥30 years (3.3% vs 0.4%) | PMC10351693 |
Characteristics associated with having no prior Hepatitis B virus infection among participants screened for the SiVET studies in Kenya and Uganda (2014–2017) | HBV infection | REGRESSION, NAIROBI | We present the results of the logistic regression analyses of having no prior HBV infection among participants who had complete data on HBsAg and HBcAb-Total (n = 1265).In the unadjusted analysis, participants from Kampala (AOR 2.19; 95% CI 1.64–2.94) and Nairobi (AOR 2.79; 95% CI 2.06–3.81) had significantly higher odds of having no prior HBV infection than participants from the two fishing communities around Entebbe. Having a formal occupation was associated with lower odds of having no prior HBV infection than having an informal high-risk occupation (AOR 0.44; 95% CI 0.29–0.67).In the adjusted analysis, when compared to the youngest age group (≤24 years), the odds of having no prior HBV infection were lower among those aged 25–29 years (AOR 0.51; 95%CI 0.36–0.71) and those aged ≥30 years (AOR 0.35; 95% CI 0.25–0.49). Taking participants from Entebbe with informal high-risk occupations as the reference group, participants had a higher likelihood of having no prior HBV infection if they had informal high-risk jobs and were either from Kampala (AOR 2.21; 95% CI 1.41–3.47) or Nairobi (AOR 2.61; 95% CI 1.72–4.00). Also, among Entebbe participants, there was no association between occupation and the likelihood of having no prior HBV infection ( | PMC10351693 |
Characteristics associated with having no prior Hepatitis B infection among participants screened for SiVET studies in Kenya and Uganda (n = 1265). | * N not equal to 1,265 because of missing data; OR = Odds ratio; CI = Confidence Interval; Ref = reference group | PMC10351693 | ||
Secondary analysis of characteristics associated with Hepatitis B infection among participants screened for the SiVET studies in Kenya and Uganda (2014–2017) | HBV infection | SECONDARY, NAIROBI | We performed a secondary analysis among 1,340 (98.1%) screened participants, with a test result for HBsAg. The analysis of HBsAg positivity showed that age group and sex were associated with living with HBV after adjustment for other demographic variables. Participants aged 25–29 years were more likely to be infected than those <25 years (AOR 2.40; 95% CI 1.07–5.89). Males were more likely than females to be living with HBV (AOR 6.34; 95% CI 1.84–39.96). While participants from Nairobi were least likely to be living with HBV in unadjusted analysis, site was no longer associated with HBV infection after adjustment for other demographic variables. Details are in “ | PMC10351693 |
Discussion | acute infection, deaths, hepatitis, HBV infection | ACUTE INFECTION, NAIROBI, HIV INFECTION, RECRUITMENT, HEPATITIS B, HEPATITIS | Overall, we found that HBV prevalence and immunity due to Hepatitis B vaccination were low among participants who were screened for SiVET studies in Uganda and Kenya with two thirds of participants having test results suggesting no prior HBV infection. We did observe significant heterogeneity among study populations, with a higher prevalence of persons living with HBV in Uganda than in Kenya. This prevalence we report is lower than that seen from recent surveys among various KPs in South Africa [A high proportion of our participants had no prior exposure to Hepatitis B with only 9 out of every 100 participants having immunity due to Hepatitis B vaccination. Despite this, they had continued sexual exposure which increases the risk of acute infection in adults and is shown to contribute 23.5% of hepatitis related deaths [Older individuals (≥25 years) had a lower likelihood of having no prior HBV infection. As with HIV infection, older age has been associated with higher HBV prevalence among KPs [Overall, being from Kampala or Nairobi irrespective of main occupation was associated with a higher likelihood of having no prior HBV infection. The likelihood of having no prior HBV infection was up to 2.5 times higher among individuals whose main job was categorized as informal high risk if they were from Kampala and Nairobi compared to their counterparts in Entebbe. A similar pattern was seen among individuals from Kampala with informal low risk jobs whose likelihood of having no prior HBV infection was higher than individuals from Entebbe with informal high-risk jobs. These findings suggest that site rather than occupation is associated with the odds of having no prior HBV infection and could be explained by the different site recruitment procedures. Entebbe recruited directly from two fishing communities, Kampala recruited from the Good Health for Women Project (GHWP) clinic serving FSWs while Nairobi recruited from the Sex Workers Outreach Program (SWOP-Kenya) clinics serving FSWs and MSM. The GHWP and SWOP-Kenya clinics had been in existence since 2008 [ | PMC10351693 |
Limitations | HBV co-infections | REGRESSION, RECRUITMENT | The results of this work are comprised of participants undergoing screening from three SiVETs, each of which had their own enrollment criteria and target populations. Because screening efforts encouraged persons without HIV to enroll, and HIV/ HBV co-infections are not uncommon, our estimates of HBV are likely underestimates, even if they might approximate what one might see when screening for an HIV vaccine trial. The results we present here are therefore likely not generalizable to the wider populations of persons not participating in clinical trials. We had missing data for some of the parameters used to ascertain HBV status due to differences in how sites screened for HBV. We therefore had 101 participants with unknown status who were not included in the logistic regression analysis. Data were also missing for some baseline variables i.e., 98 participants with known HBV status were missing education level. However, the multivariable models with and without the number of participants with missing data gave similar results. As we note above, our screening and recruitment efforts focused on persons without HIV which may account for our lower observed prevalence of HBV. | PMC10351693 |
Conclusions and recommendations | Hepatitis B, HBV infection | HEPATITIS B | HBV prevalence and immunity due to vaccination are low among potential HIV vaccine trial participants and a high proportion have no prior exposure to HBV. Younger individuals and those recruited from existing cohorts/ clinics are more likely not to have prior HBV infection. HBV screening should continue for HIV vaccine trials layered or combined with oral PrEP and, scale up of Hepatitis B vaccination to populations at risk should be accelerated and integrated within existing HIV prevention programs. HIV prevention trials should not only screen out individuals living with HBV but should also use trials as a platform to extend HBV vaccination to KPs that need it. | PMC10351693 |
Supporting information | PMC10351693 | |||
Characteristics associated with Hepatitis B surface antigen positivity among participants screened for SiVET studies in Kenya and Uganda (n = 1340). | (PDF)Click here for additional data file.(XLSX)Click here for additional data file.We also wish to acknowledge the study staff and participants. | PMC10351693 | ||
References | PMC10351693 | |||
Subject terms | nausea, neutropenia, fatigue, anemia, MIBC, muscle-invasive bladder cancer | ADVERSE EVENTS, NEUTROPENIA, ANEMIA | Cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy. Seventy-six patients were enrolled; of these, 33 achieved a cCR (43%, 95% confidence interval (CI): 32%, 55%), and 32 of 33 who achieved a cCR opted to forgo immediate cystectomy. The positive predictive value of cCR was 0.97 (95% CI: 0.91, 1), meeting the co-primary objective. The most common adverse events were fatigue, anemia, neutropenia and nausea. Somatic alterations in pre-specified genes (In a phase 2 trial, the combination of gemcitabine, cisplatin and anti-PD-1 led to a clinical complete response in 43% of patients with muscle-invasive bladder cancer, which facilitated bladder sparing and was associated with long-term bladder-intact metastasis-free survival. | PMC10667093 |
Main | MIBC, DDR, muscle-invasive bladder cancer | DNA DAMAGE, RECURRENCE | Radical cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC). However, radical cystectomy is a life-changing operation due to the need for urinary diversion and is associated with a 90-d mortality risk of up to 6–8% (ref. Given the potential to achieve a pCR with TURBT followed by neoadjuvant chemotherapy, the need for cystectomy to achieve cure in all patients has been questioned. Early single-center retrospective studies reported that long-term bladder-intact disease-free survival is achievable in a select subset of patients with MIBC treated with TURBT plus systemic therapy, and contemporary retrospective series have substantiated such resultsSingle-agent PD-1/PD-L1 immune checkpoint blockade followed by cystectomy for the treatment of MIBC has been shown to yield a pCR in 30–40% of patientsThe integration of molecular biomarkers may further improve selection of patients with MIBC who could be treated definitively with TURBT plus systemic therapy. Somatic alterations in genes encoding proteins involved in DNA damage repair (DDR) in pre-treatment TURBT tissue have been correlated with a higher pCR rate with cisplatin-based neoadjuvant chemotherapyTo further evaluate the role of TURBT plus systemic therapy as definitive treatment for MIBC, we designed a phase 2 trial integrating (1) cisplatin-based chemotherapy plus PD-1 blockade; (2) standardized clinical restaging; and (3) translational analyses seeking to explore genomic, radiologic and immunologic biomarkers to refine future patient selection for this approach. Our primary goal was to test whether uniformly assessed and consistently defined cCR could identify patients who could safely forgo immediate cystectomy. We reasoned that a potentially effective personalized risk-adapted strategy would (1) tolerate missing some patients who might have been suitable candidates to forgo immediate cystectomy in favor of maximizing identification of patients who fare well without immediate cystectomy and (2) incorporate the ability of later cystectomy to achieve favorable cancer-related outcomes in the subset of patients with a cCR who experience local recurrence after initial surveillance. Therefore, our primary objectives were to estimate the cCR rate and to assess the positive predictive value of cCR for a composite outcome measure (2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy; Extended Data Fig. | PMC10667093 |
Results | PMC10667093 | |||
Patient characteristics and treatment | Cisplatin-eligible patients with cT2–T4aN0M0 MIBC received treatment with four cycles of gemcitabine and cisplatin plus nivolumab (Extended Data Fig. Between 8 August 2018 and 24 November 2020, 76 patients were enrolled with baseline characteristics as detailed in Table Baseline patient characteristics ( | PMC10667093 | ||
Coprimary endpoint analysis | SECONDARY | The co-primary endpoint of cCR was achieved in 33 of 76 patients (43%, 95% confidence interval (CI): 32%, 55%; Fig. The median metastasis-free and overall survival for the entire study cohort was not reached at the time of the data lock (secondary endpoints). To further contextualize the prognostic impact of achieving a cCR as related to metastasis-free survival and overall survival, a post hoc landmark analysis was performed using the time of clinical restaging as ‘time 0’. On landmark analysis from the time of restaging, patients achieving a cCR experienced significantly longer metastasis-free survival and overall survival compared to patients not achieving a cCR (Fig. | PMC10667093 | |
Clinical outcomes according to cCR status | The median follow-up for patients achieving a cCR was 30 months (range, 18–42 months) at the data lock and the clinical outcomes of this group are detailed in Fig. | PMC10667093 | ||
Clinical outcomes of patients enrolled on HCRN GU16-257 achieving a cCR. | cancer | CANCER, RECURRENCE | * Patient underwent cystectomy for radiographic changes concerning for local recurrence without evidence of cancer on biopsy or final cystectomy specimen. † Patient opted for immediate cystectomy.Thirty-nine patients did not achieve a cCR, and 34 of 39 underwent cystectomy (four received off protocol radiation and one declined any local therapy). The relationship between clinical restaging results in patients not achieving a cCR and the final cystectomy pathological stage is summarized in Supplementary Table | PMC10667093 |
Safety | treatment-emergent adverse | The treatment-emergent adverse events are detailed in Extended Data Table | PMC10667093 | |
Genomic features associated with clinical outcomes | SECONDARY | In an effort to refine future selection of patients for this risk-adapted treatment approach, a secondary objective of the study was to assess whether the presence of a set of genomic alterations in baseline TURBT tissue would enhance the positive predictive value of cCR. Tumor-only targeted DNA sequencing of pre-treatment TURBT tissue was available from 73 of 76 patients (Fig. | PMC10667093 | |
Radiographic features associated with clinical outcomes | bladder tumors | BLADDER TUMORS, RESIDUAL TUMOR | Conventional radiographic assessments are largely qualitative, and bladder tumors are particularly difficult to assess given the anatomy of the bladder and challenges distinguishing post-treatment bladder wall thickening from residual tumor | PMC10667093 |
Immunological features associated with clinical outcomes | To determine whether baseline and/or on-treatment immune parameters were associated with achieving a cCR or with metastasis-free survival or overall survival, additional exploratory analyses were pursued. PD-L1 immunohistochemical staining (22C3 antibody clone) of baseline TURBT specimens was completed in a central laboratory. A higher PD-L1 combined positive score was associated with a higher cCR rate, although the relationship between higher PD-L1 expression and longer metastasis-free survival or overall survival did not achieve statistical significance (Extended Data Fig. | PMC10667093 | ||
Discussion | MIBC, tumor necrosis | RECURRENCES, TUMOR NECROSIS, METASTATIC BLADDER CANCER | To our knowledge, this is among the first prospective trials to test TURBT plus cisplatin-based chemotherapy as definitive bladder-sparing treatment for MIBC; the first to define the performance characteristics of uniformly assessed and defined cCR as a tool for patient selection for this strategy; and the first to integrate immune checkpoint blockade into this approach. Our study demonstrates that stringently defined cCR is associated with favorable survival outcomes and that prolonged bladder-intact survival is achievable in a large subset of patients with MIBC and a cCR to TURBT and gemcitabine, cisplatin, plus nivolumab.Radical cystectomy or radiation therapy are mainstays of local treatment for MIBC. However, despite such treatments, more than 50% of patients experience metastatic recurrenceAlthough the IMvigor 130 and Keynote 361 studies exploring concurrent administration of platinum-based chemotherapy and PD-1/PD-L1 blockade in patients with metastatic bladder cancer did not demonstrate improvements in survival, those studies pooled patients treated with cisplatin-based and carboplatin-based chemotherapyOur study has potential limitations. The median follow-up of patients achieving a cCR was 30 months at the time of the data lock. The vast majority of local and distant recurrences occur within 2 years of treatment in previous bladder-sparing studies of MIBC, although whether the same pattern and timing holds true for patients not undergoing cystectomy or receiving radiation is not well establishedA disconnect between clinical and pathological staging has often been cited as a barrier to TURBT plus systemic therapy as definitive treatment for MIBC, although many analyses highlighting such a disconnect have been retrospective and without uniform approaches to clinical response assessmentIntegrating pre-treatment and on-treatment biomarkers could potentially refine selection of patients achieving a cCR after TURBT plus systemic therapy for omission of additional local therapy. Mutations in a pre-specified set of genes selected based on previous workAnalysis of circulating immune parameters may facilitate biomarker discovery and insights related to the immunomodulatory effects of treatment. Mass cytometry analysis of PBMCs revealed that a higher abundance of pre-treatment naive CD4 T cells and on-treatment naive CD8 T cells was associated with longer metastasis-free and overall survival. Multiplex proteomic analysis of plasma revealed that increased on-treatment levels of cytotoxicity-related markers TRAIL, FasL and CD244 were associated with a higher likelihood of achieving a cCR. TRAIL and FasL are members of the tumor necrosis factor (TNF) superfamily and are expressed by immune effector cells, whereas CD244 is a surface receptor on natural killer (NK) cells and a subset of CD8 T cellsIn our study, neoadjuvant gemcitabine, cisplatin, plus nivolumab after TURBT was associated with a cCR rate of 43%, and clinical response assessment identified patients with particularly favorable outcomes and facilitated bladder sparing. Genomic, imaging and immunological biomarkers have the potential to refine this treatment paradigm, but they require further investigation. These findings may help advance a more personalized approach to the management of MIBC. | PMC10667093 |
Methods | PMC10667093 | |||
Study design | MIBC | HCRN GU 16–257 is phase 2, investigator-initiated, multicenter clinical trial. Cisplatin-eligible patients with MIBC enrolled at seven medical centers received treatment with gemcitabine, cisplatin, plus nivolumab (Fig. | PMC10667093 | |
Patients | vitiligo, pneumonitis, cancers, neuropathy, malignancy, interstitial lung disease, psoriasis, infection, hypothyroidism, Cancer | DISORDER, VITILIGO, CANCERS, ADVERSE EVENT, HEPATITIS B, VIRUS, PNEUMONITIS, NEUROPATHY, INTERSTITIAL LUNG DISEASE, PSORIASIS, INFECTION, HEPATITIS C, TYPE I DIABETES MELLITUS, ONCOLOGY, HYPOTHYROIDISM, AUTOIMMUNE DISEASE, CANCER | Inclusion criteria:Written informed consent and HIPAA authorization for release of personal health information before registrationAge ≥18 years at the time of consentEastern Cooperative Oncology Group (ECOG) performance status of ≤1 within 28 d before registrationHistological evidence of clinically localized muscle-invasive UC of the bladder (that is, cT2N0M0)Candidate for cystectomy as per treating physicianAdequate organ functionAdequate archival tissue identified at screening (that is, at least 15 unstained slides or paraffin block)Women of childbearing potential must have a negative serum or urine pregnancy test within 7 d before cycle 1, day 1.Exclusion criteria:Prior treatment with systemic chemotherapy for muscle-invasive UC of the bladderActive infection requiring systemic therapyPregnant or breastfeedingAny serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy or interfere with the interpretation of study resultsPrior malignancy active within the previous 3 years except for locally curable cancers that have been apparently curedSubjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition requiring only hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger are permitted to enroll.Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 d of study drug administration. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathwaysGrade ≥2 neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03)Prior radiation therapy for bladder cancerPositive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus RNA or hepatitis C antibody (HCV antibody), indicating acute or chronic infectionKnown history of testing positive for HIV or known AIDSEvidence of interstitial lung disease or active, non-infectious pneumonitis | PMC10667093 |
Treatment | toxicity | EVENTS, ADVERSE EVENT | Cycles 1–4 of treatment included gemcitabine 1,000 mg mAdverse events were graded according to the NCI CTCAE version 4.03. Adverse events were managed according to algorithms based on the specific toxicity as defined in the protocol. | PMC10667093 |
Clinical restaging and cCR definition | malignancy, tumor, tumors | RESIDUAL, TUMOR, TUMORS, METASTATIC DISEASE | After cycle 4 of gemcitabine, cisplatin, plus nivolumab, patients underwent clinical restaging including MRI of the abdomen and pelvis or CT if MRI was contraindicated and CT of the chest, rigid cystoscopy with biopsies and urine cytology. Transurethral resection of any visible tumor and/or the prior tumor site was performed. In addition, biopsies were obtained from the following sites: trigone, left, right, anterior, posterior and dome. In men, prostatic urethral biopsies were performed. A cCR was defined as meeting all of the following: (1) no evidence of malignancy on biopsy with the exception of low-grade papillary (Ta) tumors; (2) no malignant cells on urine cytology; and (3) no evidence of local or metastatic disease on cross-sectional imaging. Residual bladder wall changes on cross-sectional imaging were interpreted by the treating investigator in consultation with the local radiologist and in the context of the bladder biopsy results. A blinded post hoc central review of the restaging MRI scans was completed by two study radiologists (S.L. and B.E.A.) to assign a VI-RADS | PMC10667093 |
PD-L1 immunohistochemistry on baseline TURBT specimens | tumor | CPS, TUMOR, INFILTRATING | Immunohistochemistry for PD-L1 was performed in the Department of Pathology at the Mount Sinai Hospital using the 22C3 antibody clone. PD-L1 expression was quantified by a single genitourinary pathologist (G.K.H.) blinded to clinical outcome data using the combined positive score (CPS), defined as the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells. A cutpoint of CPS ≥ 10 was used to define ‘high’ PD-L1 expression as per previous studies in UC | PMC10667093 |
DNA sequencing of baseline TURBT specimens | Archival baseline TURBT tissue underwent tumor-only targeted DNA sequencing using the Illumina NextSeq platform (Caris Life Sciences). An Agilent custom-designed SureSelect XT assay (Caris MI TumorSeek 592-Gene NGS Panel) was used to enrich 591 whole-gene targets. Sequencing and gene variant calling were carried out as previously described; the pipeline automatically filters out known common germline population variants (that is, from databases such as dbSNP) and flags pathogenic mutations that are potentially germline | PMC10667093 | ||
Mass cytometry (CyTOF) | Mass cytometry (CyTOF) was performed on PBMCs obtained on cycle 1, day 1 and cycle 3, day 1 of treatment. PBMCs were stained with the CyTOF antibody panel detailed in Supplementary Table Astrolabe was employed for automated computational annotation (Astrolabe Diagnostics). CyTOF analysis was performed using Astrolabe annotated data and statistical modeling with R. The data were loaded into R using the package ‘orloj’. Astrolabe gating strategies were manually reviewed for a subset of samples. Data were uploaded to Cytobank for quality control analysis and visualization. | PMC10667093 | ||
Multiplex protein immunoassay | tumor | TUMOR | Plasma (cycle 1, day 1 and cycle 3, day 1) and urine (at time of restaging) were analyzed using the Olink Immuno-Oncology panel, which measures 92 proteins involved in immune response and tumor biology, using the Olink multiplex assay (Olink Bioscience) according to the manufacturer’s instructions. The Olink panel uses proximity extension assay technology, which relies on pairs of DNA-labeled antibodies that bind to target proteins and generate unique reporter molecules that can be quantified by real-time polymerase chain reaction. The Olink panel provides normalized protein expression units (NPX), which are log | PMC10667093 |
Statistical analysis | REGRESSION | The co-primary objectives of the study were to (1) estimate the cCR rate with gemcitabine, cisplatin, plus nivolumab and (2) assess the positive predictive value of cCR for a composite outcome measure of (1) 2-year metastasis-free survival in patients achieving a cCR and opting to not undergo immediate cystectomy or (2) <pT1N0 in patients with a cCR who opted for immediate cystectomy. Secondary objectives included assessing the association between genomic alterations in a pre-specified panel of genes detected in pre-treatment TURBT tissue (The sample size was based on the following assumptions: (1) patients without a cCR would not be suitable to forgo cystectomy; (2) ~40% of enrolled patients would achieve a cCR; and (3) ~35% of enrolled patients would achieve the composite outcome measure. Therefore, our assumption implied that the negative predictive value of a cCR would be 1. The sample size was based on the CI width of the positive predictive value of cCR for the composite outcome measure and generated such that the lower bound of the 95% one-sided CI exceeded 80%. This required enrollment of 68 patients, and the sample size was increased to 76 to account for potential missing data.Rates were calculated using percentages and compared among different groups using Fisher’s exact test. Time-to-event outcomes were analyzed using the Kaplan–Meier method and log-rank test. When comparing time-to-event outcomes for restaging cCR status and restaging VI-RADS, landmark analyses were conducted using the restaging times as the landmark time (that is, time 0). For analysis of multiplex protein immunoassay (Olink) data, the data were normalized with the reference samples using R software. The data distribution per sample was compared, and samples were inspected with warnings after NPX conversion. For CyTOF analysis, the data were normalized to percent of cell abundance and 95th percentile of surface protein expression. For Olink and CyTOF, differential protein expression and differential cell abundance, respectively, were calculated using a mixed effect linear model strategy to adjust for relevant clinical variables (ECOG performance status) and demographics (age, race and gender). First, the variance profiles and data distributions were explored to identify potential biases and assess the effect of relevant covariates in the analysis using the packages lme4, variancePartition and Dream. For Olink and CyTOF, quality control analysis served to identify biases such as low detection and poor sample quality. The filters included removing variables with more than 40–70% not available or under the limit of detection values. The variables were verified as linearly independent such that there was no redundancy in the data. After quality control, individual expression or abundance was modeled as a function of relevant endpoints and covariates. Differential expression or abundance analyses were performed applying a contrast matrix to each regression model (one per endpoint) and using the moderated t-statistic or log odds when appropriate. False discovery rate adjustment was performed on resulting | PMC10667093 | |
Reporting summary | Further information on research design is available in the | PMC10667093 | ||
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/s41591-023-02568-1. | PMC10667093 | ||
Supplementary information |
Supplementary Tables 1–5.Reporting SummaryClinical Trial Protocol. | PMC10667093 | ||
Extended data | PMC10667093 | |||
Schematic representation of the design of HCRN GU16-257. | MFS, muscle-invasive urothelial cancer of the bladder | BLADDER TUMOR | Patients with muscle-invasive urothelial cancer of the bladder diagnosed based on standard of care TURBT (transurethral resection of bladder tumor) received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging consisting of cystoscopy with biopsies, urine cytology, and imaging including MRI (magnetic resonance imaging) of the bladder (or computed tomography scan if MRI was contraindicated). Patients achieving a clinical complete response (cCR) were offered the option to proceed with immediate cystectomy versus proceed without cystectomy and receive an additional 4 months of single-agent nivolumab followed by surveillance. Patients without a cCR were recommended to undergo immediate cystectomy. The primary objectives were to estimate the cCR rate and to assess the positive predictive value (PPV) of cCR for a composite outcome measure (MFS, metastasis-free survival). *Patients achieving a clinical CR were offered the option to forgo cystectomy or proceed with immediate cystectomy.
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Vesical Imaging-Reporting And Data System (VI-RADS) scoring of bladder magnetic resonance imaging (MRI) post-treatment with gemcitabine, cisplatin, plus nivolumab and association with clinical outcomes. | (
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Relationship between PD-L1 immunohistochemical staining of pre-treatment transurethral resection of bladder tumor specimens (n = 59) and clinical outcomes. | (
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Peripheral blood mass cytometry (CyTOF) and association with response and overall survival. | (
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Peripheral blood protein analytes and association with response and overall survival. | (
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Extended data | is available for this paper at 10.1038/s41591-023-02568-1. | PMC10667093 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02568-1. | PMC10667093 | ||
Acknowledgements | Cancer | CANCER | This trial was funded by Bristol Myers Squibb, and translational analyses were supported by the V Foundation for Cancer Research T2019-011 (M.D.G. and J.Z.). Scientific and financial support for the CIMAC-CIDC Network is provided through NCI Cooperative Agreements U24CA224319 (to the Icahn School of Medicine at Mount Sinai CIMAC), U24CA224331 (to the Dana-Farber Cancer Institute CIMAC), U24CA224285 (to the MD Anderson Cancer Center CIMAC) and U24CA224316 (to the CIDC at the Dana-Farber Cancer Institute). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Study GU16-257 was additionally supported through the Foundation for the National Institutes of Health (FNIH), in partnership with Friends of Cancer Research. Scientific and financial support for the Partnership for Accelerating Cancer Therapies public–private partnership are made possible through funding support provided to the FNIH by AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Gilead, GlaxoSmithKline, Janssen, Novartis Institutes for Biomedical Research, Pfizer and Sanofi. Additional support for investigators included P30 CA196521 (M.D.G. and S.G.); R01 CA249175 (M.D.G.); T32 CA078207 (S.I.); NIH/LRP (S.I.); and U01 DK124165 (S.G.). This work used the services of the Tisch Cancer Institute Biorepository and Pathology Core. We thank Magdalena Thurin, Minkyung Song, Helen Chen and Goutham Reddy from NCI, Stacey Adam, Marquet Minor and Tetyana Murza from the FNIH, and Rebecca Enos from Emmes for their support. | PMC10667093 |
Author contributions | T.J., G.K., | Conception and design: M.D.G. Financial support: M.D.G. Administrative support: M.D.G. and S.I. Provision of study materials: M.D.G., S.D., K.G.C., T.B.D., J.P.C., B.O., A.D., R.M., C.K., R.B., H.X., K.N., Y.K., E.E., R.M., S.G., J.S. and S.K.P. Collection and assembly of data: M.D.G., S.D., S.I., E.G., K.G.C., S.L., B.E., T.B.D., J.P.C., B.O., A.D., R.M., C.K., T.J., M.G., R.B., H.X., K.N., Y.K., E.E., Y.N., G.I., R.C., G.K.H., R.M., M.Y., Q.Z., S.K., R.S., J.Z., S.G., J.S. and S.K.P. Data analysis and interpretation: M.D.G., S.D., S.I., E.G., K.G.C., S.L., B.E., T.B.D., J.P.C., B.O., A.D., R.M., C.K., T.J., G.K., A.H., Y.N., G.I., R.C., L.W., K.W.M., R.M.S., N.B., Q.Z., S.K., R.S., J.Z., S.G., J.S. and S.K.P. Manuscript writing: M.D.G., E.G., S.L., T.J., Y.K., M.Y., Q.Z., S.K., R.S. and J.Z. Final approval of manuscript: M.D.G., S.D., S.I., E.G., K.G.C., S.L., B.E., T.B.D., J.P.C., B.O., A.D., R.M., C.K., T.J., M.G., R.B., H.X., K.N., G.K., A.H., Y.K., E.E., Y.N., G.I., R.C., G.K.H., L.W., K.W.M., R.M.S., R.M., N.B., M.Y., Q.Z., S.K., R.S., J.Z., S.G., J.S. and S.K.P. Accountable for all aspects of the work: M.D.G. | PMC10667093 | |
Peer review | PMC10667093 | |||
Data availability | SECONDARY | In accordance with NIH’s Genomic Data Sharing Policy, the DNA sequencing data used to support the findings of this study have been deposited under controlled access in the database of Genotypes and Phenotypes (dbGaP) under accession number phs0003372. Genomic, clinical, mass cytometry and protein analyte data from this study used to support this publication will be made available upon reasonable request from a qualified medical or scientific professional for the specific purpose laid out in that request and may include de-identified individual participant data. Requests for secondary use of this data will require completing a data use agreement ( | PMC10667093 | |
Competing interests | HTG, A.H., Genotwin, T.J. | ONCOLOGY, EMD | M.D.G. has received research funding from Bristol Myers Squibb, Novartis, Dendreon, AstraZeneca, Merck and Genentech. He has served as a consultant to Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Pfizer, EMD Serono, SeaGen, Janssen, Numab, Dragonfly, GlaxoSmithKline, Basilea, UroGen, Rappta Therapeutics, Alligator, Silverback, Fujifilm, Curis, Gilead, Bicycle, Asieris, Abbvie and Analog Devices. S.D. has served as a consultant to Janssen, Ferring, Photocure, Taris, Pacific Edge, QED, Abbvie, Janssen, Bristol Myers Squibb, Sesen, Protara, Pfizer and CG Oncology. T.B.D. has served as a consultant to Astellas, AstraZeneca, Bayer, Janssen and Sanofi. R.M. has served as a consultant to Bristol Myers Squibb, Roche, Astellas and Seattle Genetics and has received research funding from Merck and Astellas. C.K. has served as a consultant to Exelixis, Sanofi, AVEO, EMD Serono and Janssen and has received research funding from Sanofi, Gilead Sciences, AstraZeneca, ESSA Pharma, Pionyr and Incyte. He owns stock in Biogen and Epic Systems. T.J. is an employee of Genentech. A.H. has served as a consultant to HTG Molecular Diagnostics and Immunorizon. L.W. is an employee of GeneDx. K.W.M. has served as a consultant to EMD Serono, Pfizer, UroGen and Riva Therapeutics, has received research support from Pfizer and Novo Ventures, has equity in Riva Therapeutics, has received writing fees from UpToDate and has received speaking fees from OncLive. He is named on an institutional patent filed on mutational signatures of DNA repair deficiency. N.B. has served as a consultant to Apricity, BreakBio, Carisma Therapeutics, CureVac, Genetech, Novartis, Primevax, Tempest Therapeutics, Dragonfly Therapeutics, BioNTech, Genotwin and Rome Therapeutics. She has received research support from Harbour Biomed Sciences and Regeneron. J.Z. is an employee of GeneDx. S.G. received research funding from Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Regeneron and Takeda. J.S. has served as a consultant or advisor for Natera, Pacific Edge, Merck, Urogen and Janssen. S.K.P. has received travel support form CRISPR Therapeutics and Ipsen. All remaining authors declare no competing interests. | PMC10667093 |
References | PMC10667093 | |||
Key Points | PMC10251208 | |||
Question | Does receipt of peer comparison (also known as social norm or relative performance) feedback on antibiotic prescribing have a significant negative impact on job satisfaction among primary care clinicians in Boston, Massachusetts, and Los Angeles, California? | PMC10251208 | ||
Findings | SECONDARY | In this secondary analysis of a randomized clinical trial conducted from November 1, 2011, to April 1, 2014, the intervention, which delivered a comparison of individual clinician performance with that of top-performing peers in monthly emails, did not reduce mean job satisfaction beyond the noninferiority margin of clinical significance. | PMC10251208 | |
Meaning | SECONDARY | These findings suggest that behavioral interventions aimed at improving performance can be designed in a way that may protect clinician job satisfaction.This secondary analysis of a randomized clinical trial examines whether a national randomized trial using peer comparison feedback to change antibiotic-prescribing behavior has a significant negative impact on physician job satisfaction. | PMC10251208 | |
Importance | Interventions that improve clinician performance through feedback should not contribute to job dissatisfaction or staff turnover. Measurement of job satisfaction may help identify interventions that lead to this undesirable consequence. | PMC10251208 | ||
Objective | To evaluate whether mean job satisfaction was less than the margin of clinical significance among clinicians who received social norm feedback (peer comparison) compared with clinicians who did not. | PMC10251208 | ||
Design, Setting, and Participants | SECONDARY | This secondary, preregistered, noninferiority analysis of a cluster randomized trial compared 3 interventions to reduce inappropriate antibiotic prescribing in a 2 × 2 × 2 factorial design from November 1, 2011, to April 1, 2014. A total of 248 clinicians were enrolled from 47 clinics. The sample size for this analysis was determined by the number of nonmissing job satisfaction scores from the original enrolled sample, which was 201 clinicians from 43 clinics. Data analysis was performed from October 12 to April 13, 2022. | PMC10251208 | |
Interventions | Feedback comparing individual clinician performance to top-performing peers, delivered in monthly emails (peer comparison). | PMC10251208 | ||
Main Outcomes and Measures | The primary outcome was a response to the following statement: “Overall, I am satisfied with my current job.” Responses ranged from 1 (strongly disagree) to 5 (strongly agree). | PMC10251208 | ||
Results | A total of 201 clinicians (response rate, 81%) from 43 of the 47 clinics (91%) provided a survey response about job satisfaction. Clinicians were primarily female (n = 129 [64%]) and board certified in internal medicine (n = 126 [63%]), with a mean (SD) age of 48 (10) years. The clinic-clustered difference in mean job satisfaction was greater than −0.32 (β = 0.11; 95% CI, −0.19 to 0.42; | PMC10251208 | ||
Conclusions and Relevance | ’ | SECONDARY | In this secondary analysis of a randomized clinical trial, peer comparison did not lead to lower job satisfaction. Features that may have protected against dissatisfaction include clinicians’ agency over the performance measure, privacy of individual performance, and allowing all clinicians to achieve top performance. | PMC10251208 |
Trial Registration | ClinicalTrials.gov Identifiers: | PMC10251208 | ||
Introduction | Many performance improvement interventions that exert social influence have shown early signs of success, | PMC10251208 | ||
Methods | This report follows the Consolidated Standards of Reporting Trials ( | PMC10251208 | ||
Study Design and Participants | Respiratory Infections | RESPIRATORY INFECTIONS | The Use of Behavioral Economics and Social Psychology to Improve Treatment of Acute Respiratory Infections Trial was a multisite, cluster randomized trial with practice as the unit of randomization.A total of 248 participants (practicing attending clinicians or advanced practice nurses) were enrolled from 47 participating outpatient clinic sites in Boston, Massachusetts, and Los Angeles, California. Prescribing data from electronic medical records for participating practices were transferred to the data coordinating center on a weekly basis. Data on race/ethnicity were not collected. Surveys were administered using Qualtrics, version XM (Qualtrics); up to 3 survey reminders were sent by email. | PMC10251208 |
Intervention | respiratory tract infections | Peer comparison feedback was delivered in monthly email messages from practice leadership during the 18-month intervention period. We assessed clinicians’ inappropriate prescribing rates within each geographic region using electronic health record data. Clinicians ranked in the lowest decile of inappropriate prescribing rates (the top-performing decile) were told via email that they were a “top performer.” The remaining clinicians were told that they were “not a top performer.” Both types of emails included the number and proportion of antibiotic prescriptions the clinician wrote for antibiotic-inappropriate acute respiratory tract infections. Those labeled “not top performers” were also shown the proportion written by top performers. Ties in rankings were allowed so any number of clinicians could be labeled “top performers.” | PMC10251208 | |
Measurement | Exit surveys, which included a question about job satisfaction, were launched 1 to 12 weeks (varying by institution) following the 18-month intervention. Thereafter, clinicians received up to 3 reminders to complete their survey by the end of 8 weeks; completion times were the same between clinicians who did and did not receive social norm feedback because randomization was stratified by institution. Responses to the following statement were measured on a 5-point Likert scale: “Overall, I am satisfied with my current job.” Responses ranged from 1 (strongly disagree) to 5 (strongly agree). | PMC10251208 | ||
Hypothesis Testing | We preregistered a noninferiority hypothesis test (Our null hypothesis is that the peer comparison intervention | PMC10251208 | ||
Sample Size | SECONDARY | This study is a prespecified secondary analysis using data from a randomized clinical trial conducted from November 1, 2011, to April 1, 2014. A total of 248 clinicians were enrolled from 47 clinics. The sample size for this analysis was determined by the number of nonmissing job satisfaction scores from the original enrolled sample, which was 201 clinicians from 43 clinics. Assuming no interaction between interventions, an 80% response rate, at least 90% clinic participation, and an intraclinic correlation of 0.07, we have 80% power to reject the hypothesis that the intervention reduces job satisfaction on average by at least one-third of a Likert point. | PMC10251208 | |
Statistical Analysis | SECONDARY | Data analysis was performed from October 12 to April 13, 2022. Analyses were completed using R, version 3.6.0 (R Project for Statistical Computing), Stata, version 16 (StataCorp LLC), and SAS, version 9.4 (SAS Institute Inc). We used the regress command in Stata to test the difference in mean job satisfaction. We also preregistered a standard null hypothesis of no difference in job satisfaction as a secondary analysis. We explored the effect of peer comparison controlling for accountable justifications and suggested alternatives and concurrent interventions using separate 2- and 3-way interaction models. We conducted a 2-tailed | PMC10251208 | |
Results | The participant response rate was 81% (201 of 248), and the clinic participation rate was 91% (43 of 47) ( | PMC10251208 | ||
Practice and Clinician Characteristics | PCP | Abbreviations: FTE, full-time equivalent; PCP, primary care practice.Mean (SD) job satisfaction was 3.73 (0.88). Prescribers randomized to peer comparison had 0.11 (95% CI, −0.19 to 0.42; | PMC10251208 | |
Discussion | Performance feedback using peer comparison is a widely used approach in health and public policy to change behavior. We rejected the hypothesis that there were negative effects on job satisfaction after a peer comparison intervention. We note that a previous study | PMC10251208 | ||
Limitations | SECONDARY | This study has some limitations. The primary limitation is that it is a secondary analysis of a randomized clinical trial. Additionally, participant enrollment and nonresponse to the survey may have introduced selection effects, although study enrollment (70%) and the survey response rate (81%) were relatively high. Survey response latency may have affected perceptions of the intervention. Another limitation is that the survey question was a single, one-time measure that may not accurately reflect job satisfaction. | PMC10251208 | |
Conclusions | The conflicting findings between the 2 studies suggest that the details of how peer comparison is implemented may be crucial for its success and impact on clinician well-being. | PMC10251208 | ||
Objective: | migraine | MIGRAINE | Design a feasible study to assess the efficacy and safety of Craniosacral therapy (CST) in the treatment of migraine, using a rigorous and innovative randomized controlled study design involving complementary light-touch sham treatments (CLST) as an attention control intervention. | PMC10637508 |
Methods: | migraine, Headache, Anxiety, headache | MIGRAINE, SECONDARY, ADVERSE EVENTS | This was a single-center, randomized, cross-over placebo-controlled experimental design. A total of 87 participants who suffered migraine attacks from 4 to 9 per month were randomly assigned into either 2 weekly units of CST or CLST for 4 weeks. And then the 2 groups were crossed and continued treatment for 4 weeks plus a follow-up observation for 4 weeks. As the primary outcome measures, Headache Impact Test-6 (HIT-6) and headache frequency were assessed every 4 weeks (at baseline, week 4, week 8 and week 12). The secondary outcome was the scores of Headache Disability inventory (HDI) and the Hamilton Anxiety Scale (HAMA) as well as the adverse events. | PMC10637508 |
Results: | headache | All 87 individuals had been screened for eligibility, of which 60 were licensed for the study. The difference of HIT-6 and headache frequency between the 2 groups was not significant at the baseline. But the headache frequency and HIT-6 of 2 groups were all declined respectively after the CST at week 4 (group A) and week 8 (group B) than before ( | PMC10637508 | |
Conclusion: | migraine, headache-related disability | MIGRAINE | The results indicated that standardized CST was both effective and safe in alleviating the migraine intensity and frequency as well as the headache-related disability. Further larger research is needed. | PMC10637508 |
1. Introduction | migraine, treat).Migraine, Headache, Migraine | MIGRAINE, CHRONIC DAILY HEADACHE, MIGRAINE, HEADACHE DISORDERS | Migraine is a common disabling condition that spans the globe.According to the definition of International Headache Society, migraine is a recurrent headache disorder manifesting in attacks lasting 4 to 72 hours (when untreated or unsuccessfully treat).Migraine affects people quality of life and work ability and social activities. Symptoms of migraine are still difficult to control, despite the modification of diet, sleep, aerobic exercise and relaxation as well as the availability of medications are both used for clinical treatment. Furthermore, overuse of medication for the treatment of frequent episodic migraine is a risk factor for developing chronic daily headache. | PMC10637508 |
2. Materials and methods | PMC10637508 | |||
2.1. Design | migraine | MIGRAINE | This was a single-center, randomized, cross-over, placebo-controlled trial design, completed by neurologists and trained professional rehabilitation therapist. We design a feasibility study to assess the efficacy and safety of CST in the treatment of migraine, using a rigorous and innovative randomized controlled study design involving CLST as an attention control intervention. Figure Research process. | PMC10637508 |
2.2. Participants | Headache | HEADACHE DISORDERS, HEADACHE DISORDERS | The neurologist used guidelines from the international classification of headache disorders third edition to select patients from hospital where he works and invited them to participate in the study.Eligibility of subjects for clinical effectiveness trial of Craniosacral therapy.International Classification of Headache Disorders, defined by expert members of the International Headache Society. | PMC10637508 |
2.3. Criteria for inclusion and exclusion | Criteria for inclusion (Table | PMC10637508 | ||
2.4. Randomization and blinding | First, after signed the concealed allocation protocol, the subjects were randomly divided into 2 groups to receive different non-pharmacological treatments. We adopted simple randomization and used the number table grouping method for grouping: group A for CST and group B for CLST. Instead, they were told that 2 different CST techniques would be tested. After 4 weeks, group A and group B were swapped. Second, throughout the study period, the investigator assessing the outcome remained unaware of the allocation of subjects. Third, the statistician who analyzed the results was also blinded to the group assignment. | PMC10637508 | ||
2.5. Intervention | headache | GROUP B | We chose 3 rehabilitation therapists who had received unified craniosacral treatment training for craniosacral treatment and 3 other rehabilitation therapists who also had received unified other treatment training for sham treatment. This research design period lasted 12 weeks, and every 4 week was 1 round of treatment. CST or CLST twice a week, 1 hour each time. HIT-6 and headache frequency were assessed at baseline and right after every treatment round. In the first round, groups A received conventional medicine plus CST and group B received conventional medicine plus CLST. And then interchanged between Group A and Group B in the second round of treatments. Neither group received treatment in the third round, just waiting for the fourth evaluation. | PMC10637508 |
2.5.1. Craniosacral therapy. | cranial muscle fascia | Since the brain, spinal cord, cranial muscle fascia and all related structures are the content of the craniosacral system, its restrictions or imbalance will directly affect any or all aspects of the performance of the central nervous system. | PMC10637508 | |
2.5.2. Complementary light-touch sham treatments. | CLST was applied on standardized anatomic areas, equal to those treated with CST. The CLST was also completed by 3 therapists who had received unified training. The CLST protocol was designed to mimic the length of the CST protocol in the treatment session, the sequence of interactions with the therapist, and the terms of the overall treatment experience. | PMC10637508 | ||
2.6. Outcome measures and study instruments | PMC10637508 | |||
2.6.1. Primary outcome: HIT-6 and Headache frequency. | migraine, headache | MIGRAINE | The HIT-6, which has been translated 27 different languages so far,The 6-item headache impact test.According to the Delphi study by Luedtke, HIT-6 and headache frequency are the most useful and meaningful outcome for research on the effectiveness of non-pharmacological intervention for headache and migraine. | PMC10637508 |
2.6.2. Secondary outcome: The scores of HDI and the HAMA; the safety and feasibility. | PMC10637508 | |||
The Henry Ford Headache Disability Inventory (HDI): | Headache, headaches, headache | HDI can be used to periodically evaluate a patient with headache and can be used to determine the effectiveness of a management strategy over time. It is a 40-item self-assessment scale designed to facilitate the clinician assessment of the patient perception of the functional and emotional aspects of their headaches (Fig. The Henry Ford Headache Disability Inventory (HDI). | PMC10637508 | |
Hamilton Anxiety Scale (HAMA): | migraine, anxiety | MIGRAINE | Studies have found that anxiety, especially general anxiety, is very common in migraine patients. | PMC10637508 |
The safety and feasibility: | ADVERSE EVENTS, SIDE EFFECT | Safety assessment was obtained by direct contact with research staff or by asking patients about the frequency and the severity of side effect before and after each treatment round. Besides, patients were also required to record side effects and simultaneous treatment and medicine use in daily records. No serious adverse events were reported. | PMC10637508 | |
2.7. Statistical analyses | The SPSS 17.0 for Windows was used to perform statistical analyses. All values were expressed as the mean ± standard deviation. The data of 2 groups were analyzed using the repeated measurement analysis of variance. Differences are considered statistically significant when | PMC10637508 | ||
3. Results | All 87 individuals had been screened for eligibility, of which 60 were licensed for the study. Evenly divided into group A and group B. Figure Our rehabilitation center and professional therapist. | PMC10637508 | ||
3.1. Baseline data | migraine, SD | MIGRAINE | The age of the subjects ranged from 20 to 50 years old and the average age of group A was 40.7 ± 9.6 years. 12 cases were male; The average age of group B was 38 ± 10.3 years. 11 cases were male. The commonly related factors of migraine were also shown in Table Baseline characteristics.Date is presented as mean ± standard (SD); Number (n). | PMC10637508 |
3.2. Primary outcome: HIT-6 and Headache frequency | PMC10637508 | |||
3.2.1. HIT-6. | The HIT-6 are presented in Table HIT-6 of the 2 groups of patients before and after treatment.Table 3 presents the mean and standard deviation of the total score for the HIT-6 for every group at each time point. There was no difference in HIT-6 between the 2 groups at baseline. Compare with the CLST, the HIT-6 of the groups were significantly decreased after the CST at the week 4 (group A) and week 8 (group B). While the change was not obvious after CLST in group A at week 8 and group B at week 4 compared with prior to treatment.This figure visually shows the change trend of HIT-6 with over time. The score of group A decreased significant from baseline to week 4 and group B decreased obvious from week 4 to week 8. | PMC10637508 | ||
3.2.2. Headache frequency. | Headache, headache | According to the criteria for inclusion, the headache frequency of subject was from 5 to 9 per month. The frequency and trend of headache are shown in Table Headache frequency changes.Table 4 present the Mean and standard deviation of headache frequency at baseline, after the first round of treatment (week 4) and the second round of treatment (week 8) and 4 wk follow-up observation (week 12) (This figure visually shows the change trend of headache frequency with over time. The change of headache frequency in group A from baseline to week 4 and the change of group B from week 4 to week 8 were significant. On the contrary, the change of group A from week 4 to week 8 and the change of group B from baseline to week 8 were not obvious. It indicates that the headache frequency of both groups was significantly reduced after the CST in 2 groups while not obvious after CLST. CLST = complementary light-touch sham treatments. CST = Craniosacral therapy. | PMC10637508 |
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