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Univariate and multivariate COX regression analyses | MCC | MCC | The 6107 MCC patients included in this study were randomly divided into two groups in the ratio of 7:3 using R software (version 4.1.3). Data for patients in the training set were used to build the nomograms ( | PMC10620318 |
Construction of prognostic nomogram | Demographic variables (race, gender, age) and indicators with | PMC10620318 | ||
Result | PMC10620318 | |||
Patient characteristics | A total of 6107 COCA patients were obtained from the SEER database. Of these, 4276 were classified into the training cohort and 1831 in the validation group. Of the patients in the training cohort, 488 patients (11.4%) in the training cohort were < 50 years old, the majority (75.9%) were white, while the rest were black or other races, and 2154 (50.3%) were males. For the validation cohort, 916 patients (50%) were males, and 192 patients (48.0%) were < 50 years of age (Table The demographics and pathological characteristics of patients included in the present study | PMC10620318 | ||
Univariate and multivariate COX regression analysis | tumor | BRAIN METASTASIS, TUMOR, PRIMARY TUMOR, LUNG METASTASIS, BONE METASTASIS, REGRESSION, LIVER METASTASIS | Firstly, one-way COX regression analysis for age, race, gender, tumor primary site, tumor size, TNM stage of the 8th edition of AJCC, serum carcinoembryonic antigen, nerve invasion, lymph node metastasis, liver metastasis, lung metastasis, bone metastasis, and brain metastasis were performed. Several factors, including primary tumor site, tumor size, ethnicity, serum carcinoembryonic antigen, nerve invasion, lymph node metastasis, liver metastasis, lung metastasis, bone metastasis, and brain metastasis, were significantly associated with COCA prognosis (Univariate and multivariate analyses of factors linked to COCA prognosis* | PMC10620318 |
Prognostic nomogram construction | Nomograms for predicting 6 and 18 months of OS of COCA were constructed using data for patients in the training set (Fig. Nomograms for predicting the OS of COCA patients. | PMC10620318 | ||
Nomogram calibration and validation | The C-index was used to compare the performance of the nomograms. Particularly, the C-index of the training cohort without stratification by age and the validation cohort was 0.79 (95% CI 0.77–0.81) and 0.81 (95% CI 0.77–0.84), respectively. In the early-onset COCA training set cohort, validation cohort C-index was 0.95 (95% CI 0.91–0.99), 1. In the late-onset COCA training cohort, the validation cohort C-index was 0.72 (95% CI 0.69–0.75), 0.75 (95% CI 0.71–0.79), respectively. The C-index of the nomogram for predicting the OS of patients grouped by the TNM staging based on the 8th edition of AJCC guidelines was 0.68 (95% CI 0.65–0.71). ROC curves were plotted to assess the performance of the models (Fig. ROC for the 6- and 18-month prognosis prediction of the nomograms and the TNM staging system. Calibration curves of the nomogram and TNM staging system. | PMC10620318 | ||
Survival analyses | The overall risk scores (with the median score as the critical value) of each prognostic factor included in the three nomograms were calculated, and patients were divided into low-risk and high-risk groups. The KM curves were plotted (Fig. The KM curves for OS prediction of the TNM staging system. | PMC10620318 | ||
Discussion | cancer, deaths | CANCER | COCA is the fifth leading cause of cancer-related deaths worldwide (Sung et al. The dataset not stratified by age in this study is one in which the study cohort was not grouped based on age. Many previous studies have demonstrated that for cancer patients, older adults have a shorter OS survival than their younger opposites (Tai et al. In this study, the relationship between sex and prognosis of COCA patients was not significant. However, demographic variables such as sex and race are one of essential variables in cancer treatment (Goggins and Lo The TNM staging system is the standard method for staging COCA (Hari et al. This study had several limitations. First, given that it was a retrospective study, selection bias in the patient selection process cannot be ruled out. In addition, due to the limited clinical information on patients in the SEER database, more valuable clinical factors, such as specific radiation treatment regimens, surgical access, were not considered in the analysis. Finally, the accuracy of our nomogram was not validated with external data. To override this limitation, our study cohort was divided into the training and validation cohort in a ratio of 7:3, in which the 30% of the population was used for internal validation. The results of the internal validation demonstrated the robustness of the model. Despite these drawbacks, our study has some clear advantages. First, this study included sufficient data, which increased the reliability of our findings. Second, we constructed three nomograms simultaneously, which not only made the results more comparable but also illustrated some differences in the factors that impact prognosis between early-onset COCA and late-onset COCA. Third, the model's accuracy was validated, further demonstrating the stability and reliability of the constructed models. Finally, the dynamic nomograms could predict the OS of COCA patients at all ages. | PMC10620318 |
Author contributions | All authors contributed to the research design. YZY designed and prepared the manuscript; YZY and PX performed the analysis, and CZ read and approved the final manuscript. | PMC10620318 | ||
Funding | This study was supported by Minsheng Science and Technology Program Joint Program (2021JH2/10300106). | PMC10620318 | ||
Data availability statement | The dataset supporting the conclusions of this paper is included in the material of this paper. | PMC10620318 | ||
Declarations | PMC10620318 | |||
Conflict of interest | The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10620318 | ||
Ethics approval and consent to participate | Not applicable. | PMC10620318 | ||
Consent for publication | All authors consent to the publication of this study. | PMC10620318 | ||
References | PMC10620318 | |||
Key Points | PMC10570919 | |||
Question | SOFT TISSUE SARCOMA, STS | Is intratumoral toll-like receptor 4 agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) injection with radiotherapy an effective and feasible treatment for patients with advanced soft tissue sarcoma (STS)? | PMC10570919 | |
Findings | tumors | TUMORS, STS | In this phase 1 nonrandomized controlled trial of 12 patients with advanced STS, intratumoral GLA-SE with radiotherapy was well tolerated, with all patients achieving local control of injected tumors. Durable local response was associated with expansion of intratumoral T-cell receptor clones, and these specific clones were detectable in the systemic circulation following intratumoral GLA-SE. | PMC10570919 |
Meaning | T-cell | SOFT TISSUE SARCOMA | These findings suggest that intratumoral IT GLA-SE with radiotherapy is a promising combination treatment associated with systemic expansion of putative antitumor T-cell clones in advanced STS.This nonrandomized controlled trial of patients with advanced soft tissue sarcoma analyzed the immunomodulatory effects of intratumoral glycopyranosyl lipid A in stable-emulsion formulation with concurrent radiotherapy. | PMC10570919 |
Importance | SOFT TISSUE SARCOMAS | Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts. | PMC10570919 | |
Objective | STS | To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions. | PMC10570919 | |
Design, Setting, and Participants | sarcoma | SARCOMA, STS | This phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022. | PMC10570919 |
Interventions | Two doses of IT GLA-SE (5 μg and 10 μg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion. | PMC10570919 | ||
Main Outcomes and Measures | Primary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes. | PMC10570919 | ||
Results | REGRESSION, ADVERSE EVENT | Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, −25%; range, −100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion −39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting T | PMC10570919 | |
Conclusions and Relevance | In this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted. | PMC10570919 | ||
Trial Registration | ClinicalTrials.gov Identifier: | PMC10570919 | ||
Introduction | cancers | SOFT TISSUE SARCOMA, CANCERS, NEOPLASMS, STS | Soft tissue sarcomas (STSs) are a heterogeneous group of more than 50 distinct mesenchymal neoplasms together composing 1% of all cancers. Despite incremental advances, median overall survival for patients with metastatic STS remains approximately 24 months.As a key exploratory end point, we characterized changes in the T-cell receptor (TCR) repertoire following GLA-SE. Metrics evaluating TCR clonality and diversity in tumor-infiltrating lymphocytes (TILs) have been associated with patient outcome in a number of settings. | PMC10570919 |
Methods | PMC10570919 | |||
Study Design and Patients | tumor, sarcoma, hematologic, kidney, and hepatic function, Hutchinson Cancer, Cancer | SARCOMA, TUMOR, CANCER | This open-label, phase 1 nonrandomized controlled trial of IT GLA-SE was conducted at the Seattle Cancer Center Alliance and Fred Hutchinson Cancer Research Center from November 17, 2014, to March 16, 2016, in accordance with International Conference on Harmonization Guidelines for Good Clinical Practice and the Eligible patients were 18 years or older with metastatic sarcoma and at least 1 palpable, superficial tumor safely accessible for bedside injection that would also be irradiated. Patients were required to have adequate hematologic, kidney, and hepatic function. Patient race and ethnicity information were collected by self-report. A complete list of eligibility criteria is provided in eFigure 1 in | PMC10570919 |
Treatment | tumor | TUMOR | Patients received planned, standard-of-care palliative radiotherapy to the injected superficial tumor as part of normal clinical care. Radiation was given within 2 weeks after starting GLA-SE injections. Although the goal radiation dose was 50 Gy or higher, the administered dose was at the discretion of the treating radiation oncologist.The treatment schema is provided in eFigure 2 in | PMC10570919 |
Clinical Assessments | Tumors, tumor | TUMORS, ADVERSE EVENT, SYSTEMIC DISEASE, TUMOR | The primary objective was to assess the safety and tolerability of IT GLA-SE in combination with radiotherapy using the Common Terminology Criteria for Adverse Events, version 5.0. Secondary objectives were to assess the clinical efficacy of local and systemic disease control as well the immunologic effects. Assessment of tumor responses was performed for both target and noninjected lesions according to RECIST (Response Evaluation Criteria in Solid Tumors), version 1.1. Imaging and biopsies were performed at baseline before treatment and after the eighth dose. After this, imaging was performed every 6 weeks for 4 scans, then every 12 weeks after that, until progression. | PMC10570919 |
TLR4 Staining Analysis | tumor | TUMOR | Slides from the formalin-fixed paraffin-embedded tumor blocks were stained with hematoxylin-eosin and with antibodies to TLR4 (MAB14783; R&D Systems) and analyzed by Mosaic Laboratories. A pathologist confirmed tumor presence using hematoxylin-eosin, and immunohistochemical findings were scored on a positivity scale of 0 (absent) to 3+ (strong). Banked tumor formalin-fixed paraffin-embedded blocks from previous institutional review board–approved protocols were also stained. | PMC10570919 |
Immunologic Correlative Studies | Rapid expansion protocol of TILs, | PMC10570919 | ||
Statistical Analysis | Statistical analysis was conducted from August 2016 to September 2022. All enrolled patients who received at least 1 dose of IT GLA-SE were included in the safety analysis. Descriptive statistics were used to summarize baseline patient characteristics, safety, clinical response, and immunologic response variables. Local response was measured as percent change of the maximum dimension of the target lesion. For local response comparison between target lesions and concomitant irradiated or untreated lesions, means were calculated by pooling local response at last follow-up for all lesions among evaluable patients (n = 3). Statistical analysis was performed using Microsoft Excel, version 16 (Microsoft Corp) and GraphPad Prism, version 9 (GraphPad Software Inc). | PMC10570919 | ||
Results | PMC10570919 | |||
Patients | sarcoma, synovial sarcoma, tumor | TUMOR, DISEASE, SARCOMA, SYNOVIAL SARCOMA, LEIOMYOSARCOMA | Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female and 4 [33%] male; 9 [75%] White, 1 [8%] Asian, and 2 [17%] with no race or ethnicity reported) with metastatic sarcoma with a superficial tumor amenable to bedside IT injection concurrent with radiotherapy given over 2 weeks were enrolled in the trial. Six patients were treated in the 5-μg cohort, and after observing no dose-limiting toxic effects, 6 additional patients were treated in the 10-μg cohort. One patient was not enrolled because of screening failure.Six patients (50%) had leiomyosarcoma; the next most common subtype was synovial sarcoma (2 [17%]). The mean (SD) largest dimension of the injected tumor was 5.4 (3.6) cm. Patients had a median of 5 sites (range, 2-9 sites) of disease and 3.5 lines of treatment (range, 0-5 lines) before enrollment ( | PMC10570919 |
Patient Characteristics at Baseline | myalgia, fatigue, infections, pain, rashes | ONCOLOGY, ADVERSE EVENT, INJECTION SITE REACTION, INFECTIONS | Abbreviation: ECOG, Eastern Cooperative Oncology Group.Data are presented as number (percentage) of patients unless otherwise indicated.Seven patients (58%) had at least a grade 1 adverse event (AE), with only 1 patient (8%) in the 5-μg cohort having grade 2 AEs (myalgia and fatigue). The most common AE reported was fatigue in 5 patients (42%), followed by injection site reaction (2 [17%]); all injection site reactions were pain related. No serious infections or rashes were reported. There was no association between the dose of IT GLA-SE and the frequency or severity of AEs ( | PMC10570919 |
Number of Patients With TRAEs | ADVERSE EVENTS, ADVERSE EVENT, ADVERSE EVENT | Abbreviation: TRAE, treatment-related adverse event.Grading of adverse events was based on Common Terminology Criteria for Adverse Events, version 5.0. | PMC10570919 | |
Local Response | tumor, sarcoma | TUMOR, SARCOMA | All patients achieved local control of the injected target lesions after 8 doses. One patient (8%) had complete response in the injected tumor, whereas 4 other patients (33%) had durable local response with greater than 25% size reduction. In this small cohort, there was no apparent association between local response and dosage, sarcoma subtype, previous therapies, number of metastatic sites, age, or sex (eTable and eFigure 4 in | PMC10570919 |
Local Response of Lesions Receiving Intratumoral Glycopyranosyl Lipid A in Stable-Emulsion Formulation | tumor | DISEASE, TUMOR, BEST | A, Spider plot demonstrating change from baseline of tumor size and its durability beyond the trial period. B, Best percent change (which was at the end of follow-up time point for all patients) by cohort and histologic subtype.To analyze the contribution of IT GLA-SE in combination therapy, we identified 3 patients with evaluable concomitant lesions during the trial follow-up period who received radiotherapy alone or no local therapy. Although other patients also had multiple sites of disease, they lacked lesions that underwent radiotherapy alone during the trial follow-up period. Durable local responses were observed only in irradiated lesions that also received IT GLA-SE. By pooled mean percent change at last follow-up, lesions treated with IT GLA-SE and radiotherapy had deep size reductions (−69%), single-modality irradiated lesions also decreased (−39%), and untreated lesions increased (+69%) ( | PMC10570919 |
Local Control After Intratumoral Glycopyranosyl Lipid A in Stable-Emulsion Formulation (IT GLA-SE) Compared With Concomitant Lesions | tumor, tumors, leiomyosarcoma | TUMOR, TUMORS, LEIOMYOSARCOMA, REGRESSION, UNDIFFERENTIATED ROUND CELL SARCOMA | A, Percent change in size of lesions at end of same follow-up period for tumors receiving IT GLA-SE plus radiotherapy (orange) vs tumors receiving radiation only (blue) or no local treatment (green). B, Representative computed tomograms of lesions at baseline and at last follow-up in a patient with undifferentiated round cell sarcoma and complete regression of tumor after IT GLA-SE and patient with leiomyosarcoma −79% in size after IT GLA-SE. | PMC10570919 |
Changes in the Tumor Microenvironment of Injected Tumor | Where sufficient quality tissue was available for evaluation of spatial architecture (n = 7), multiplex immunohistochemical analysis was performed on pretreatment and posttreatment samples ( | PMC10570919 | ||
Local Immune Infiltration After Intratumoral Glycopyranosyl Lipid A in Stable-Emulsion Formulation (IT GLA-SE) in Durable Responders | tumor, sarcomas | HEAT, TUMOR, INFILTRATION, SARCOMAS | A, Multiplex immunohistochemical analysis found a detectable increase in CD4 and CD8 T-cell infiltration after treatment with IT GLA-SE. One patient had a detectable increase in CD4 T-cell infiltration from 11% to 34% of all cells counted, in addition to an increase in CD8 infiltration from 0.3% to 3.4%. Another patient had a detectable increase in CD8 T cells (3% to 22% of all cells counted) with a relative decrease in the proportion of T-regulatory cells (scale bars = 100 μm). B, Top clonotypes after IT GLA-SE. Tumor-infiltrating lymphocytes (TILs) were present in 1 patient, with red denoting clonotypes also present in pretreatment TILs. Inset boxes indicate breakdown of specific T-cell receptor (TCR) β DNA sequences coding for same variable amino acid region (red denotes dominant sequence). C, Matched single-cell TCR α and TCR β sequences and their gene expression heat map from posttreatment peripheral blood mononuclear cells. Green and yellow columns on left denote clonotypes expanded in posttreatment TILs. Color bar denotes standardized We investigated whether clinical outcomes were associated with the tumor’s TLR4 expression. We performed TLR4 immunohistochemical analysis across multiple histologic subtypes of banked untreated sarcomas (n = 34); the mean positivity rate was 59% (range, 0%-100%) (eFigure 7A-B in | PMC10570919 |
Changes to TCR Repertoire in TILs Following GLA-SE | inflammation, tumor | INFLAMMATION, TUMOR, INFILTRATION | To delineate whether the increased T-cell infiltration was due to a generalized inflammation vs clonal expansion against putative tumor antigens, we analyzed TILs, generated from core biopsy samples and expanded ex vivo, using TCR sequencing. In total, 10 patients had evaluable TILs from both pretreatment and posttreatment samples. Although there was no discernible increase in TIL clonality after IT GLA-SE among all patients (mean [SD], 0.11 [0.09] before treatment and 0.16 [0.11] after treatment), increased clonality was observed in patients with local durable response (from 0.10 to 0.20), as opposed to those with limited response (from 0.07 to 0.06) (eFigure 8 in The greatest increase in TIL clonality was seen in a patient with durable local response) (eTable in Of the dominant TCR clonotypes, CASSDGTGFSSGYTF was present at a very low frequency IT GLA-SE in only 1 unique DNA rearrangement (14 template reads, <0.01% relative frequency); after IT GLA-SE, this TCR rearrangement expanded to become the dominant clone, contributing more than 30 000 template reads using 13 different variable gene families (To phenotype these dominant clones, we performed single-cell sorting and targeted gene reverse transcription using nested polymerase chain reaction in posttreatment PMBCs, where we found these TCRs frequently present. Multiple singlets with matching TCR β sequence were isolated from posttreatment PBMCs. By RNA sequencing, we found high levels of CD4 | PMC10570919 |
Circulating T-Cell Response | inflammation, tumor, tumor necrosis, death | REGRESSION, INFLAMMATION, TUMOR, TUMOR NECROSIS | We were interested in whether TCR sequences dominant in TILs became more prevalent in the circulation as part of a systemic antitumor response. The PBMCs from all patients underwent TCR sequencing before and after completion of study treatment. Of particular interest was 1 patient who had a complete local response with no radiographically detectable lesion at the end of the trial period (making posttreatment biopsy impossible). After localized injection with IT GLA-SE, the overall circulating PBMC clonality increased 5-fold (0.057 to 0.279). Three clones were present in the pretreatment TILs and PBMCs; these clones underwent clonal expansion in the posttreatment PBMCs and represented 11% of all circulating TCRs (supporting data in eFigure 10 in Because 1 patient had dominant clones with markers for TWe then asked whether the T cells with convergent TCRs constituted a functional effector population. To test this, PBMCs from durable local responders were stimulated with CD3/CD28 beads and then sorted using intracellular staining for tumor necrosis factor α and granzyme B along with CD4 and CD8 labeling (eFigure 11 in We sought to test for a difference in inflammatory proteins and circulating checkpoints in durable responders to evaluate whether this was different compared with minimal responders following IT GLA-SE treatment. Indeed, there were increased markers of both inflammation and checkpoint markers in the responders. For instance, 1 patient with complete regression of treated tumor had a log-fold increase of 0.6 for CD28, 0.6 for lymphocyte activation gene 3 protein, and 0.4 for programmed cell death ligand 1, whereas another patient (with best local response of −17%) had log-fold changes of 0.1, −0.1, and 0, respectively (eFigure 12 in | PMC10570919 |
Discussion | METASTASIS | Radiation therapy is an effective tool in the management of symptomatic metastasis for STS.We saw large increases in the clonality of PBMCs, including expansion of TCR sequences observed in TILs, suggesting additional systemic potential for this therapy. | PMC10570919 | |
Limitations | This study as some limitations. Because this was a phase 1 dose-escalation trial, the findings are preliminary. In addition, the number of patients was limited and not powered to evaluate clinical efficacy, and there was no placebo control group. | PMC10570919 | ||
Conclusions | tumor | TUMOR | In this phase 1 nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was safe, with preliminary evidence of efficacy in the injected tumor. However, further study is warranted. In patients with durable local response, there was evidence of intratumoral T-cell clonal expansion of both preexisting and novel TCRs; these unique TCRs were then detected in circulating PBMCs after treatment and had a T | PMC10570919 |
Background | fractures, intertrochanteric fracture, pain | Hip fractures are common in elderly patients. The surgery is usually delayed due to underlying conditions, and pain control is crucial while the patient is cleared for surgery. In this randomized controlled trial (RCT) study, we hypothesized that the application of skin traction in patients with intertrochanteric fracture does not significantly change the Visual Analogue Score (VAS) of pain. | PMC9834036 | |
Methods | fractures, drug addiction, swelling | SKIN | This is a prospective, single institution, parallel randomized controlled trial. Two hundred and twenty-nine patients with isolated intertrochanteric fractures were enrolled in the study. Patients with neurologic issues, drug addiction, scars or swelling, or vascular issues at the site of skin traction application were excluded from the study. Patients were divided into two groups: group A included 97 patients, and group B included 95 patients. Skin traction was applied for group A, while only a soft pillow was put beneath the patients’ knees in the other group. The VAS score was measured after the diagnosis, two hours before the operation, and 24 h after the surgery. The morphine dosage administered per day was documented for both groups. | PMC9834036 |
Results | fractures, postoperative delirium | After excluding patients with postoperative delirium, 154 patients (55 males and 99 females) with isolated intertrochanteric fractures (69 right-sided and 85 left-sided), and a mean age of 70 ± 10 remained in the study. There were no significant differences between the two groups regarding age, gender, and mean time from injury to admission ( | PMC9834036 | |
Conclusion | fractures, intertrochanteric fractures | Pre-operative skin traction application affected neither the patients' VAS scores nor the mean morphine dosage per day in patients with isolated intertrochanteric fractures. Our data does not support the routine application of pre-operative skin traction in patients with intertrochanteric fractures. | PMC9834036 | |
Trial registration | The project was registered in the Iranian Registry of Clinical Trials (registration reference: IRCT20180729040636N3, registration date: 01/07/2020). | PMC9834036 | ||
Level of evidence | 1. | PMC9834036 | ||
Keywords | PMC9834036 | |||
Background | delirium, tractions, pain, fractures, trauma | COMPLICATIONS | Hip fractures are common in orthopedic trauma, and current practice and literature suggests improved outcomes with early operation [In addition, patients with severe pain during hospitalization are at higher risk for experiencing delirium and other post-operative complications [Wennberg et al. reported that supplementation with low dose fascia iliaca compartment block, in addition to analgesia (intravenous morphine and oral paracetamol) provided better preoperative pain relief in 27% of patients with hip fractures within two hours compared with placebo [Multiple studies in the literature have reported the neutral effect of skin traction application on preoperative pain relief in patients with hip fractures [Despite this evidence, skin traction is routinely applied in many hospitals as a preoperative pain management technique [To the best of our knowledge, skin traction’s effect on pain relief in patients with specifically intertrochanteric fractures (as the most common type of hip fractures) has been discussed in only two other studies in the literature [We analyzed this effect via a parallel randomized controlled trial in this study. The null hypothesis of this research is that there would be no significant differences in terms of the Visual Analogue Scale (VAS) score and administered morphine dosage between the patients who underwent skin tractions and the control group (without skin-traction). | PMC9834036 |
Methods | fracture, postoperative delirium, intertrochanteric fractures, pain | SECONDARY, COMPLICATIONS | This randomized controlled trial is designed, conducted, and written based on the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement [Patients who consented to the study (192 patients) were then randomized to two groups by a medical student (S.KH.) who used random allocation software with an allocation ratio of one [The whole procedure was explained to the patients to obtain written consent. Because skin traction is impossible to hide from both the patients and the medical staff, patients and medical staff were not blinded to the study. However, as traction was removed before the patients’ entrance to the operating room, the surgeon (M.M.) was blinded and was unaware of the group to which the patient was allocated before the surgery. One surgeon (M.M.) for all the patients performed the surgery. Two different surgeries were performed for the patients: extramedullary fixation (dynamic hip screw) and intramedullary nail (Gamma nail) fixation. Also, all the patients were followed up (measuring VAS scores and documenting morphine dosage and any complications) by one orthopedic resident (M.S.) and one trained nurse (T.R.) to reduce the potential performance bias. The data analyst of the study was also blinded by not mentioning which group of the patients underwent skin-traction application. Patients were excluded from the study if they refused to continue the trial at any stage. After undergoing surgery, thirty-eight patients experienced postoperative delirium. These patients were also excluded from the study as their altered level of consciousness could affect their reported VAS scores. In the end, the data of seventy-eight patients in group A and seventy-six patients in group B were entered for the final statistical analysis (Fig.
CONSORT flow diagram depicting the number of patients allocated to each group of patients at different study stepsTable
The comparison of patients’ characteristics between the two groups70 ± 10.2(40–92)70 ± 9.8(40–91)71 ± 10.6(46–92)6.8 ± 2.3(1.0-13.3)7.1 ± 2.4(1.0-13.3)6.5 ± 2.2(1–12)5.6 ± 1.4(2–9)5.6 ± 1.3(3–9)5.6 ± 1.5(2–9)
Bar chart comparison between the two groups regarding gender. In group
Bar chart comparison between the two groups regarding the fracture side. In group The severity of the pain was measured based on VAS scores in patients within the first hour of diagnosis before skin traction application, two hours before the operation (after skin traction application and before patients’ transfer to the operating theater), and 24 h after the procedure. The study’s primary outcome was the effect of skin traction application on the VAS score of patients with intertrochanteric fractures. The secondary outcome of this study was the effect of skin traction on the mean administered intravenous morphine dosage for these patients per day.The sample size was calculated to be at least 42 in each group using the confidence interval of 95% and the power of study of 90% using the following formula [Where α = 0.05, β is the conventional multiplier for power (90% in our study). ZStatistical analysis was done using SPSS version 26, Chicago. Independent samples t-test, chi-square test, and repeated measures Analysis of Variance (ANOVA) tests were used for the statistical analysis. A | PMC9834036 |
Discussion | allergy, tamponade, AVN, DVT, occlusion of the vascular, fracture, pulmonary suppression, intertrochanteric fractures, femoral neck fractures, hip fracture, thromboembolic, avascular necrosis, femur fractures, fractures, intertrochanteric hip fractures, delirium, pain, constipation, femoral fractures, collum femoris fractures, non-union | INTRAOPERATIVE COMPLICATIONS, STILL, ALLERGY, COMPLICATION, AVASCULAR NECROSIS, PRESSURE ULCERS, UTI, DECUBITUS ULCERS, DISEASES, COMPLICATIONS, DVT | In our study, no significant difference was found in VAS score values and the mean morphine dosage administered per day between the patients with intertrochanteric fractures who underwent skin traction and the control group without traction. Therefore, in terms of pain alleviation, applying skin traction for these patients was only an extra burden on the patients and the caregivers. This is an important finding, as the standard protocol in many countries is to apply skin traction for all patients with intertrochanteric fractures [Before the introduction of fixation devices, treatment for intertrochanteric fractures was completely non-operative, consisting of prolonged bedrest (10 to 12 weeks) in traction until fracture healing occurred. It goes without mentioning that this approach was time-consuming and accompanied different complications, including decubitus ulcers, joint contractures, thromboembolic complications, and increased mortality rate. Since then, and with the introduction of fixation devices, there have been significant improvements in the management of intertrochanteric fractures [Interestingly, no explanation regarding the rationale behind skin traction application for patients with specifically intertrochanteric fractures has been given to the best of our knowledge.There are, however, several theories in the literature. One theory, in patients with proximal femoral fractures, is that the skin-traction application decreases the chance of instant pain and future non-union and avascular necrosis (AVN) by preventing the external rotation of the fractured site, the occlusion of the vascular supply, and the risk of tamponade. It has also been suggested that patients would have a better range of motion in the no traction group, allowing them to move their legs in a position with the slightest intracapsular pressure and, therefore, less pain [based on a Cochrane review article done by Handoll et al., a well-designed clinical trial is needed, especially for specific fracture types, to evaluate the cost-benefit ratio for traction application in patients [Intertrochanteric fractures are more common in patients ageing 65 and older. Pharmackokinetics and pharmacodynamics are more complex in elderly patients and they usually experience higher peak effect and longer duration of actions of opioids. This could potentially lead to higher complication rates in terms of delirium, constipation, pulmonary suppression, dependence, etc. [In addition, most of the studies on pain management in these patients are focused on the post-operative pain, as if patients’ preoperative pain is not recognized as serious pain. While in a recent study conducted by Unneby et al. even though all of the patients received femoral nerve blockades and proper intravenous analgesics, the preoperative pain perceived by patients was describes as “Hovering between heaven and hell” meaning that their pain intensity ranged from having no pain to the worst pain they had ever experienced [Rasi et al. conducted a similar clinical trial to ours with a smaller cohort on 40 patients with intertrochanteric fractures. They divided patients into two groups, each consisting of 20 participants with intertrochanteric fractures, and measured their VAS scores multiple times until 24 h postadmission. They reported that only the last VAS score at the end of the 24 h postadmission between the two groups was significant, but interestingly there was no significant difference between the two groups in terms of analgesic administration [Kobayashi et al. performed a retrospective comparative cohort study on 56 patients with intertrochanteric fractures. Eighteen patients underwent skin traction application; for the rest, the skin traction was not applied. In their study, there was no significant difference between the two groups in terms of preoperative pain at 12 h before surgery (measured by Verbal Rating Score (VRS)). Still, the VRS of the patients for whom skin traction was applied were significantly lower than others at 24–60 h after admission. However, interestingly, the two groups did not have any significant differences in terms of analgesic needs based on patients’ requests [Rosen et al. randomly allocated 100 patients (55 patients with femoral neck fractures and 45 with intertrochanteric fractures) into skin-traction and pillow placement groups. Their study noted better immediate pain relief in the group without traction. On the other hand, they found out that if patients had mean initial VAS scores of more than five, the patients who underwent skin traction experienced slightly more pain reduction [Saygi et al. divided 108 patients with hip fractures (intertrochanteric fractures and collum femoris fractures) into three groups: in group one, two-kg skin traction was applied; in group two, skin traction without weight was applied; and in group three, a pillow was put beneath the fractured limb. They evaluated the traction’s placebo effect, and better pain relief was obtained in the group with the placebo. They believed their result was due to semiflexion and external rotation and the placebo effect of the without-weight traction kit [We also measured the postoperative VAS scores, which were not reported in either of the mentioned studies, as we hypothesized that the placebo effect of skin traction might affect the pain perception in patients postoperatively. Interestingly, the postoperative VAS scores in both groups were significantly lower than the preoperative measurements. This can be because of the fixation of the fracture, postoperative analgesics administered to the patients or the mental relief for them undergoing the ultimate treatment. It has been suggested that patients’ satisfaction does not always reflect the quality of pain management but rather patients’ expectations and perceptions [Anderson et al. studied 252 patients with different types of proximal femur fractures. They randomly allocated the patients to skin traction and the control group with a nurse-free bed (method of nursing the injured limb was not specified in this study). They reported no differences in pain suffered, analgesia injection, frequency of pressure ulcers, or ease of operations between these two groups [Over the years, multiple studies reported that skin traction might not affect the severity of the pain and the dosage of required analgesics for patients with different types of hip fractures [There is an agreement in the literature that skin traction does not cause short-term severe complications for patients with different types of hip fractures. In addition to the surgery and hospitalization related complications (UTI, DVT, PE), pressure ulcers, mechanical shearing, allergy to the strapping, and blockage of blood supply to the affected limb are reported as direct complications of skin traction [In addition, the mean time from admission to surgery in all the patients (which in our study equals to the length of time that patients were in skin traction) was 5.6 ± 1.4 days, and there was no significant difference between the two groups in terms of length of time from admission to surgery.Early surgery has been reported to be associated with fewer in-hospital complications, improved functional outcomes, increased return to independent living, and decreased overall mortality [Beaupre at al. reported that 20 to 40 h of delay in surgery was associated with highest survival rate in patients older than 80 years of age; however, they mentioned that in patients who are 60 years old or younger, surgery can be delayed without any decrease in mortality rate. Therefore, they suggested that sub-prioritization of patients should be based on patients characteristics, rather than the national benchmarks [In an observational study on 83,727 patients with hip fracture performed by Leer-Salvesen et al., it was reported that delay to surgery of more than 48 h was associated with increased three day mortality, and 1 year mortality. Also, patients with delay to surgery of more than 24 h, experienced more intraoperative complications. In their study, the mean pre-hospital delay was six hours, and the mean in-hospital delay was 22 h. They reported that there was no significant effect of total delay to surgery as long as the patients underwent medical intervention within 48 h postadmission; however, mortality increased in patients who were operated on after 48 h of admission. Even though they adjusted their results based on patients’ fracture types, they ultimately suggested that preoperative patient stabilization should not be used as an argument to delay surgical intervention [To improve the surgical outcomes, many countries have established time to surgery benchmarks for patients with hip fractures, which reflect the quality of care. For example, within 48 h and 36 h of admission have been set as the national benchmarks in Canada and the UK respectively. Unfortunately, there is no such national time to surgery benchmarks in our country, which could be one of the reasons behind the observed long delay in surgery in our study. Especially, surgical interventions for patients with stable intertrochanteric hip fractures are not considered urgent, and patients might not be prioritized for immediate surgeries; considering that skin traction and morphine administration are currently the only methods of pain alleviation in our country, prolonging the time to surgery period could potentially cause further delirium and other opioid related complications in these patients. We believe that introducing time to surgery benchmarks in the national hip fracture approach protocols would be a critical step toward improving the surgery outcomes and patients’ satisfaction.In addition, even though patients with intertrochanteric hip fractures are usually older and more susceptible to experiencing severe forms of COVID-19 due to their background diseases, no prioritization was made for this group of patients in our hospital during the COVID-19 pandemic. Malik-Tabassum et al. performed an observational study on patients with different types of hip fractures in the UK, and compared the patients outcomes during 50 days of COVID-19 pandemic (period C) to two same dates within the past 2 years of the study before the pandemic (periods A and B). They reported that the mean length of inpatient stay during period C was significantly shorter than periods A and B; however, there was no significant difference in complication rates, return to the OR, and 30 day mortality rate, and the proportion of the patients discharged to their pre-admission residence during all three periods. They also mentioned that during period C, a multidisciplinary decision was made to prioritize surgery for patients with hip fractures despite the lack of available operating room’s capacity. In addition, they reported that no member of the on-call structure, junior ward cover, or provision of orthogeriatrc care was redeployed to other specialties [Based on a systematic review written by Abou-Setta et al. most of the common pain control strategies for patients with hip fracture have low to moderate effects, and the evidence on pain management after hip fractures is surprisingly sparse [Our study had some limitations. Due to the COVID-19 pandemic, we decreased the number of VAS measurements to protect our personnel and patients from unnecessary contacts. In addition, even though everyday emphasis was made on not using any other analgesics, there was no controlling for the use of non-opioid/narcotic pain relief medications during both pre- and post-operative periods by patients separately. Also, although we evaluated many patients with specifically intertrochanteric fractures, we did not separate patients with different types of surgery approaches for intertrochanteric fractures (extramedullary fixation (dynamic hip screw) and intramedullary nail (Gamma nail) fixation surgeries); however, we compared the duration of surgery for both groups. As mentioned in the results section, their difference was not statistically significant, meaning the two groups probably had the same heterogeneity in terms of intertrochanteric fracture surgery types. In addition, we did not have enough time to follow up with the patients to report the surgery’s long-term complications. This, however, seems to be a limitation in many previous studies [ | PMC9834036 |
Conclusion | fractures, ’ pain, intertrochanteric hip fractures | In conclusion, in our research, skin traction application affected neither the patients’ mean VAS scores nor the mean morphine dosage administered daily in patients with isolated intertrochanteric fractures. Considering the limited hospital time and resources and its burden on both patients and medical staff, we recommend removing skin traction from the routine protocols for patients with intertrochanteric hip fractures, and considering other potential options for patients’ pain relief instead. | PMC9834036 | |
Acknowledgements | Not applicable. | PMC9834036 | ||
Authors' contributions | All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Hossein Akbari Aghdam, Mehdi Motififard, Navid Gharib Gashteh Shahi, Mohammad Saleki Mehrjardi, Tayebe Rezaei, and Sara Kheiri. The first draft of the manuscript was written by Sara Kheiri and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. | PMC9834036 | ||
Funding | This study was not funded by any individual or any organizations. | PMC9834036 | ||
Availability of data materials | The datasets generated and/or analyzed during the current study are not publicly available due to patients’ privacy but are available from the corresponding author on reasonable request. | PMC9834036 | ||
Declarations | PMC9834036 | |||
Ethics approval and consent to participate | The study was performed in line with the principles of the Declaration of Helsinki. Ethical approval was obtained from the research ethics committee of Isfahan University of Medical Sciences. The project was registered in the Iranian Registry of Clinical Trials (registration reference: IRCT20180729040636N3, registration date: 01/07/2020).All patients signed an informed consent form prior to their participation in the study. | PMC9834036 | ||
Consent for publication | Not applicable. | PMC9834036 | ||
References | The authors declare that they have no conflict of interest/ competing interests. | PMC9834036 | ||
Background | depression, anxiety | Collaborative care (CC) could improve outcomes in primary care patients with common mental conditions. We assessed the effectiveness of a transdiagnostic model of telephone-based CC (tCC) delivered by lay providers to primary care patients with depression, anxiety, or at-risk drinking. | PMC10517649 | |
Methods | depression, anxiety, depressive symptoms | PCP | PARTNERS was a pragmatic trial in 502 primary care adults presenting with depressive symptoms, anxiety symptoms, or at-risk drinking randomized to (1) usual care by primary care providers (PCPs) enhanced with the results of computer-assisted telephone-based assessments (at baseline and 4, 8, and 12 months later) (enhanced usual care [eUC]) or (2) tCC consisting of eUC plus frequent telephone coaching and psychoeducation provided by mental health technicians who also communicated to the PCP recommendations from a psychiatrist for evidence-based pharmacotherapy, psychotherapy, or, when indicated, referrals to mental health services. The primary analysis compared the change on the 9-item Patient Health Questionnaire (PHQ-9) in participants presenting with depression ( | PMC10517649 |
Results | depression, anxiety | There were no treatment or time×treatment effects between tCC and eUC on PHQ-9 scores for patients with depression during the 12-month follow-up. However, there was a treatment effect (tCC > eUC) on GAD-7 scores in those with anxiety and a time×treatment interaction effect on the number of weekly drinks (tCC > eUC) in those with at-risk drinking. | PMC10517649 | |
Conclusion | depression, anxiety | DISORDERS | Implementing transdiagnostic tCC for common mental disorders using lay providers appears feasible in Canadian primary care. While tCC was not better than eUC for depression, there were some benefits for those with anxiety or at-risk drinking. Future studies will need to confirm whether tCC differentially benefits patients with depression, anxiety, or at-risk drinking. | PMC10517649 |
Abrégé | PMC10517649 | |||
Contexte | d’anxiété ou à risque de consommation d'alcool | Les soins collaboratifs (SC) pourraient améliorer les résultats chez les patients des soins de première ligne souffrant d’états mentaux communs. Nous avons évalué l’efficacité d’un modèle transdiagnostique de SC par téléphone (SCt) dispensé par des prestataires non professionnels à des patients de première ligne souffrant de dépression, d’anxiété ou à risque de consommation d'alcool excessive. | PMC10517649 | |
Méthodes | d’anxiété ou une consommation à risque | PARTNERS était un essai pragmatique mené auprès de 502 adultes recevants des soins de première ligne qui présentaient des symptômes dépressifs, d’anxiété ou une consommation à risque et qui ont été randomisés à : (1) des soins usuels par des prestataires de première ligne (PPL) améliorés par les résultats d’évaluations par téléphone assistées par ordinateur (au départ puis 4, 8, et 12 mois plus tard) (eSU); ou (2) SCt consistant en eSU et un fréquent encadrement par téléphone et psychoéducation donnés par des Techniciens de santé mentale (TSM) qui ont aussi communiqué aux PPL les recommandations d’un psychiatre à l’égard de la pharmacothérapie fondée sur des données probantes, de la psychothérapie ou, le cas échéant, des renvois aux services de santé mentale. La première analyse comparaît le changement du Questionnaire sur la santé du patient (QSP-9) chez les participants présentant une dépression ( | PMC10517649 | |
Résultats | Il n’y avait pas d’effet de traitement ou d'interaction temps par traitement entre SCt et eSU aux scores QSP-9 pour les patients souffrant de dépression durant le suivi de 12 mois. Cependant, il y avait un effet de traitement (SCt > eSU) aux scores TAG-7 chez ceux souffrant d’anxiété et un effet d’interaction temps par traitement sur le nombre de consommations hebdomadaires (SCt > eSU) chez ceux à risque de boire. | PMC10517649 | ||
Conclusion | d’anxiété ou à risque de consommation | Mettre en œuvre des SCt transdiagnostiques pour les troubles mentaux communs avec l’aide de prestataires non professionnels semble faisable dans les soins de première ligne canadiens. Bien que SCt n’ait pas mieux réussi que eSU pour la dépression, il y avait certains bénéfices pour ceux souffrant d’anxiété ou à risque de consommation excessive. Les futures études devront confirmer si SCt bénéficiera différentiellement les patients souffrant de dépression, d’anxiété ou à risque de consommation excessive. | PMC10517649 | |
Introduction | Depression, disability, anxiety, chronic disease | CHRONIC DISEASE | Depression, anxiety, and at-risk drinking are leading causes of disability worldwide.Collaborative care (CC) is a complex intervention based on the chronic disease management model. | PMC10517649 |
Methods | comorbidity, posttraumatic stress disorder, anxiety, cognitive impairment, bipolar disorder, psychotic disorders, depression, obsessive–compulsive disorder | DISORDER, RECRUITMENT, REGRESSIONS, ADVERSE EFFECTS, SECONDARY, REMISSION, BLIND, PCP, REGRESSION | The methods of the study have been publishedAll participants were recruited in primary care clinics in urban areas, suburban locations, and rural areas across Ontario (Canada) with all study activities conducted remotely by phone from a central office in Toronto. All participants signed an informed consent form approved by the Research Ethics Board at the Centre for Addiction and Mental Health, Toronto, Ontario. The trial was registered on ClinicalTrials.gov (Identifier: NCT02345122) on January 26, 2015.The main inclusion criteria were age 18 years and older; receiving care at 1 of the participating clinics; self-referring or being referred by a PCP to the study because of depression, anxiety, or at-risk drinking; and ability to converse in English by telephone. The main exclusion criteria were lifetime diagnoses primarily reported by participants, including psychotic disorders, bipolar disorder, obsessive–compulsive disorder, or posttraumatic stress disorder; current substance use disorder other than alcohol use disorder; cognitive impairment with a score of 16 or above on the Blessed Orientation-Memory Concentration test (BOMC)Research Associates (RAs) administered by telephone to all participants a comprehensive assessment at baseline, 4, 8, and 12 months later using the Behavioral Health Laboratory (BHL) software.Participants assessed at baseline to have depression (defined as a PHQ-9 score ≥10), anxiety (defined as a GAD-7 score ≥10), or at-risk drinking (exceeding the Canadian Guidelines for safe drinking, which are based on the number of drinks or bingesParticipants randomized to tCC were assigned to a trained bachelor-level MHT (i.e., a “lay provider”During the initial weekly, then bi-monthly, and finally monthly phone calls, MHTs also helped CC participants to identify resources (e.g., apps and community-based services) and provided monitoring including the administration of the PHQ-9, GAD-7, or an inquiry about the number of drinks, as relevant. MHTs also monitored treatment adherence and adverse effects and provided continuing psychoeducation related to the participant's conditions and their treatment.The RAs assessed the participants randomized to eUC by phone with the same BHL software at the same time points. The results of these symptom assessments were e-faxed to PCPs, but no recommendations were provided. PCPs managed these participants as they saw fit. To maintain the blind, eUC participants were also contacted by an MHT after the completion of each assessment, and they were briefly informed about the results of their assessment and told that they would be contacted again in 4 months.The primary outcome measure was the change in PHQ-9 from baseline to 12 months in those presenting with depression (i.e., those with a PHQ-9 ≥10 at baseline). Because of the transdiagnostic recruitment strategy, preplanned secondary outcome measures included change in GAD-7 from baseline to 12 months in those presenting with anxiety (i.e., those with a GAD-7 score ≥10 at baseline); change in the number of weekly drinks from baseline to 12 months in those presenting with at-risk drinking (i.e., those exceeding the Canadian Guidelines for safe drinking at baseline); and the documentation of initiation and adequacy of antidepressant treatment using the Antidepressant Treatment History FormAdditional preplanned outcomes included change in health-related quality of life and functioning in the whole sample as measured by the VR-12; rates of response or remission for depression in the depression group (defined as PHQ-9 score <10 and <5, respectively) or for anxiety in the anxiety group (defined as GAD-7 score <10 and <5, respectively), and decrease in the number of weekly drinks to meeting the guidelines for safe drinking.The main analyses compared changes from baseline to 12 months between the 2 treatment groups with linear contrasts of estimated means for the 3 main outcome measures (i.e., PHQ-9, GAD-7, and number of drinks). Accounting for the clustering within subjects and sites, mixed models assessed changes in depression or anxiety scores and changes in health-related quality of life and functioning. Because of skewed distribution, a generalized estimating equation (GEE) assessed changes in the number of drinks. Both mixed models and GEE were specified with a time-by-group interaction, where time was considered categorical. Given the high rates of comorbidity, the 3 models adjusted for baseline PHQ-9 scores, GAD-7 scores, and number of drinks. A similar approach was used for the analysis of changes in VR-12 scores. Logistic regressions compared rates of remission, response, or safe drinking at 12 months in the 2 treatment groups. We used multiple imputation to impute missing values for response and remission at 12 months. Remission and response were the dependent variable of our logistic regression to look at treatment-group differences for these outcomes. A logistic regression assessed whether the proportion of participants reporting receiving treatment differed in the 2 treatment groups. Rates of initiation and adequacy of antidepressant treatment documented in health records were compared with Fisher tests. The analyses of response and remission rates were conducted using Mplus, and all other analyses using SAS System 9.4.We had planned to recruit a sample of 1,000 participants that should have provided enough power to detect any clinically meaningful effect of the intervention. Since we were able to randomize only half of this planned sample and a post-hoc power calculation is not statistically sound, we estimated the detectable effect size, given the size of our sample and the characteristics of our model. Considering 80% power and significance level of 0.05, the detectable effect size was a difference between treatment groups in changes from baseline to 12 months of 1.85 for the PHQ-9, 1.90 for the GAD-7, and 5.7 drinks per week. This calculation was conducted using our data and a series of 1,000 Monte Carlo simulations for each outcome with the R package SIMR. | PMC10517649 |
Primary and Secondary Outcomes in Each Diagnostic Group | SE | For the primary clinical outcome (i.e., change in PHQ-9 scores in participants with a PHQ-9 score of ≥10 at baseline), the test for the contrast between the two treatment groups was not significant (mean (SE) difference between treatment groups in change in PHQ-9 score from baseline to 12 months: −0.19 (0.66); PHQ-9 scores in the 366 participants with PHQ-9 ≥10 at baseline (187 in the telephone collaborative care group and 179 in the enhanced usual care group).For a change in GAD-7 in participants with a GAD-7 score of ≥10 at baseline, the test for the contrast between the 2 treatment groups was significant (mean (standard error, SE) difference in change in GAD-7 score from baseline to 12 months: 1.47 (0.67), GAD-7 scores in the 298 participants with GAD-7 ≥10 at baseline (151 in the telephone collaborative care group and 147 in the enhanced usual care group).For the number of weekly drinks in participants with at-risk drinking, the contrast was not significant (ratio of per cent changes in the number of daily drinks from baseline to 12 months: 0.89 (95% CI, 0.63 to 1.27), t(368) = −0.63, Estimates of the effect sizes of the continuous measures were: PHQ-9: Cohen's d = 0.057; 95% CI, −0.29 to 0.404; GAD-7: Cohen's d = 0.38; 95% CI, −0.036 to 0.795; number of weekly drinks: Cohen's d = −0.099; 95% CI, −0.352 to 0.154.Number of weekly drinks in the 176 participants with at-risk drinking at baseline (95 in the telephone collaborative care group and 81 in the enhanced usual care group). | PMC10517649 | |
Initiation or Change in Antidepressant Treatment | The review of health records showed higher rates of documentation of initiation of antidepressants (Fisher's | PMC10517649 | ||
Quality of Life and Functioning in the Whole Sample | There was a significant time effect for VR-12 mental scores ( | PMC10517649 | ||
Response and Remission Rates | depression, Depression, Anxiety, anxiety | EVENT, REMISSION, REGRESSION, EVENTS, RESOLUTION | Inferential results related to logistic regression modelling of response and remission rates are presented in Rates (Denominator/Numerator) of Response or Remission for Depression, or Anxiety, and Resolution of At-Risk Drinking.Comparison of Rates of Response or Remission for Depression, or Anxiety, and Resolution of At-Risk Drinking.See text for definitions of depression, anxiety, at-risk drinking, remission, response, and safe drinking.*Odds of the outcome event in the enhanced usual care group divided by the odds in the collaborative care group: an odds ratio below 1 indicated more events happening in the collaborative care group.**This statistic is calculated as the log odds divided by its standard error and the | PMC10517649 |
Discussion | anxiety, psychiatric, depressive symptoms, depression, adjustment disorders | DISORDER, REMISSION, PCP | In this RCT of over 500 primary care patients with symptoms of depression, anxiety, or at-risk drinking, compared with eUC, a novel, low-cost, transdiagnostic tCC intervention delivered by lay providers did not result in a larger improvement in depression symptoms in those presenting with depression at baseline or in health-related quality of life and functioning in the whole sample. In those presenting with anxiety, tCC yielded a larger improvement in anxiety symptoms. While tCC did not affect the proportion of participants who had transitioned from at-risk drinking to safe drinking at the end of the 12-month study, it was associated with a faster transition. Participants randomized to tCC were more likely to have antidepressants initiated and to receive adequate antidepressant treatment than those randomized to eUC. These findings suggest that tCC delivered by lay providers is feasible in primary care and may benefit some patients with anxiety or at-risk drinking. These findings are also relevant in the context of the COVID-19 pandemic, which has led to a higher prevalence of anxiety symptoms and substance misuse and a rapid increase in virtual health care.Improvement in depressive symptoms and rates of depression response or remission were high in both groups; contrary to our hypotheses, they were not significantly different in the tCC or eUC groups. This is despite the fact that those receiving tCC were more likely to be prescribed an adequate antidepressant trial. This finding is inconsistent with similar previous studies.The positive effect of our active intervention on anxiety symptoms is consistent with a previous trial of a telephone-based tCC for 329 primary care patients with anxietySimilarly, in a recent large RCT in primary care patients with depression or anxiety, sertraline was superior to placebo for anxiety symptoms but not depressive symptoms.Our results also add to the limited literature on CC interventions for alcohol use disorder. Two published RCTs of (face-to-face) CC for alcohol use disorder have reported conflicting results.Our study has both strengths and limitations. Although we only randomized half of the planned sample, the relatively large sample size and high retention rates (68.5% overall) provided sufficient power to detect clinically meaningful differences. Selecting participants based on referrals from their PCP and their scores on the PHQ-9 or GAD-7 rather than formal psychiatric diagnoses has some pragmatic advantage (i.e., it better reflects primary care practice). However, it may have resulted in the inclusion of participants with adjustment disorders or subsyndromal depression, both of which have been shown to resolve with the passing of time or placebo treatment,In conclusion, the findings of our RCT, taken together with the results of other CC trials, support the feasibility of implementing transdiagnostic tCC delivered by lay providers in primary care. However, while patients with anxiety or at-risk drinking benefitted from tCC compared to eUC, this was not the case for those with depression. This negative result goes against our hypothesis that the crucial “ingredient” of the active intervention would be the MHT. Given the marked improvement in depressive symptoms with both tCC and eUC, future studies of CC for depression need to assess the benefits and cost-effectiveness of its specific components, in particular, MBC. | PMC10517649 |
Supplemental Material | PMC10517649 | |||
sj-docx-1-cpa-10.1177_07067437231156243 - Supplemental material for A Collaborative-Care Telephone-Based Intervention for Depression, Anxiety, and at-Risk Drinking in Primary Care: The PARTNERs Randomized Clinical Trial | Depression, Anxiety, P. | MITCHELL | Click here for additional data file.Supplemental material, sj-docx-1-cpa-10.1177_07067437231156243 for A Collaborative-Care Telephone-Based Intervention for Depression, Anxiety, and at-Risk Drinking in Primary Care: The PARTNERs Randomized Clinical Trial by M. Ishrat Husain, David J. Rodie, Athina Perivolaris, Marcos Sanches, Allison Crawford, Kyle P. Fitzgibbon, Andrea Levinson, Rose Geist, Paul Kurdyak, Brian Mitchell, David Oslin, Nadiya Sunderji, Benoit H. Mulsant and in The Canadian Journal of Psychiatry | PMC10517649 |
References | PMC10517649 | |||
Background | hypertension, weight loss | HYPERTENSION | Edited by: Paul H. Lee, University of Southampton, United KingdomReviewed by: Arkers Kwan Ching Wong, Hong Kong Polytechnic University, Hong Kong SAR, China; Weidan Cao, Washington State University, United StatesThis article was submitted to Public Health Education and Promotion, a section of the journal Frontiers in Public HealthDespite the increasing popularity of mHealth, little evidence indicates that they can improve health outcomes. Mobile health interventions (mHealth) have been shown as an attractive approach for health-care systems with limited resources. To determine whether mHealth would reduce blood pressure, promote weight loss, and improve hypertension compliance, self-efficacy and life quality in individuals with hypertension living in low-resource rural settings in Hubei, China. | PMC10014612 |
Methods | hypertension | HYPERTENSION | In this parallel-group, randomized controlled trial, we recruited individuals from health-care centers, home visits, and community centers in low-resource rural settings in Hubei, China. Of 200 participants who were screened, 148 completed consent, met inclusion criteria, and were randomly assigned in a ratio of 1:1 to control or intervention. Intervention group participants were instructed to use the Monitoring Wearable Device and download a Smartphone Application, which includes reminder alerts, adherence reports, medical instruction and optional family support. Changes in the index of Cardiovascular health risk factors from baseline to end of follow-up. Secondary outcomes were change in hypertension compliance, self-efficacy and life quality at 12 weeks. | PMC10014612 |
Results | Participants ( | PMC10014612 | ||
Conclusions | hypertension, weight loss | UNCONTROLLED HYPERTENSION, HYPERTENSION | Among participants with uncontrolled hypertension, individuals randomized to use a monitoring wearable device with a smartphone application had a significant improvement in self-reported hypertension compliance, self-efficacy, life quality, weight loss and diastolic blood pressure, but no change in systolic blood pressure compared with controls. | PMC10014612 |
Introduction | hypertension, weight loss, Hypertension, cardiovascular and cerebrovascular events | CHRONIC DISEASES, CARDIOVASCULAR DISEASE, HYPERTENSION, HYPERTENSION | Hypertension is the most common chronic condition for cardiovascular and cerebrovascular events worldwide, affecting 32.6% of US adults, and has an estimated annual medical expenses exceeding $50 billion (Many types of intervention methods have been conducted to improve therapeutic targets and BP control. Systematic reviews summarizing more than 3 decades of research advocate for specific lifestyle modifications in populations with high risk of cardiovascular disease (With the rapid rise and popularity in mobile phone use, mobile health (mHealth) could become a potential way to address several health-care system constraints in low and middle income countries, such as limited medical resources, overburdened health-care workforce, and an increasing prevalence of chronic diseases (In our research, we aimed to investigate whether mHealth including wearable monitoring device support home-based self-monitoring weekly counseling phone calls and advice for lifestyle modification could reduce BP, promote weight loss, and improve hypertension Compliance, self-efficacy and quality of life in adults with hypertension living in low-resource rural settings in China. | PMC10014612 |
Methods | PMC10014612 | |||
Study design | Hypertension, hypertensive | RECRUITMENT, HYPERTENSION | The Self-Monitoring Intervention Programme for Hypertension Control was a randomized trial conducted among 6 primary care centers within a remote mountainous districts of Hubei province, China. Details of the Program's study design and organizations have been published elsewhere (All the selected primary care centers were located in a poor rural area and provided free medication and health care to hypertensive patients. Three centers were assigned to the mobile health intervention and the other 3 centers to usual health care. All participants were included consecutively to avoid selection bias. Given the nature of the behavioral intervention, no action was taken to balance the recruitment for individuals that refused consent. | PMC10014612 |
Conceptual framework | We adopted an integrating of constructs adapted from the following conceptual models: the Task-Technology Fit (Conceptual framework for designing mHealth solutions. | PMC10014612 | ||
Study population | death, cognitive deficit, cognitive dysfunction | HYPERTENSION | Eligibility criteria were an age of more than forty, definite diagnosis of hypertension: Systolic blood pressure (SBP) ≥140 mmHg and/or Diastolic blood pressure (DBP) ≥90 mmHg or being treated with antihypertensive medication, no cognitive deficit and able to possess communication proficiency to carry out study tasks. Participants were excluded if they had cognitive dysfunction, developed serious health conditions that led to hospitalization or death, or had no smart phones to perform the mobile healthcare. Moreover, written informed consent was obtained from all participants during screening.Study data were collected at baseline and at 12 weeks. The mHealth intervention program included education of healthcare providers, adherence to drug treatment, home-based lifestyle modification, and a mobile health intervention. | PMC10014612 |
Patient recruitment and randomization | EVENTS | Participants were recruited though the cooperation of local Health and Family Planning Committee (HFPC), which composed of a diverse group of community leaders, township health centers personnel. These cooperative relationships were maintained with regular health advocacy meetings, face-to-face contact, and HFPC events, as described elsewhere (Upon receipt of the Bluetooth-enabled BP monitor, potentially eligible individuals were provided with a written instruction manual on how to set up the monitor and properly take a BP measuring. The BP monitor has been approved by BP associations for its accuracy in home use, as described elsewhere ( | PMC10014612 | |
Intervention | hypertension | HYPERTENSION | The mobile health intervention was the key element, with a complementary text messaging, BP warning, and home-visited intervention. The research team members, who were part of the staff of the local primary care centers, were trained in interactive intervention techniques, performing wearable device, measuring BP, providing life-style modification skills based on the Change Model Stages (All participants were given written information about hypertension and health promotion, and continued to receive routine hypertension management from local clinical centers. Each intervention group participants received a home-based BP monitor wearable wristband that stored and uploaded BP data to a secure website | PMC10014612 |
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