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Informed consent | Informed consent was obtained from all subjects involved in the study. | PMC10117252 | ||
Institutional review board statement | The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Centro Hospitalar de São João. (Approval code: 11/2019, approval date: 15 February 2019). Trial registration number NCT03974477 ( | PMC10117252 | ||
References | PMC10117252 | |||
Highlights | lung cancer | LUNG CANCER |
Our model including six epidemiological components was successfully validated on both internal and external validation.Risk stratification by the model showed significantly different survival patterns even after discharge.Three well-developed interfaces are friendly to both physicians and patients for prognosis-related conversations.
Our model with easily accessible variables showed its robustness in inferring its predictive value with respect to in-hospital mortality of lung cancer patients.The model is highly applicable in follow-up.Its applications are useful to clinical in the assistance of strategic planning and the improvement of end-of-life care. | PMC10451707 |
1. Introduction | lung cancer | LUNG CANCER | In 2022, there were approximately two million new cases of lung cancer diagnosed in the U.S. [For decades, cutting-edge studies in lung cancer treatment focusing on molecular insights, especially in immune checkpoint inhibitors, have resulted in remarkable findings [The scientific development in screening and treatment of lung cancer brings about early detection and lower mortality, whereas it also puts new challenges to healthcare services. On the one side, there is a limit of studies for the estimation of cost-effectiveness to age ranges of lung cancer screening [There are some researches revealing the correlation between lung cancer and other factors such as sex [ | PMC10451707 |
2. Materials and Methods | PMC10451707 | |||
2.1. Data Processing | tumor, primary lung tumors | TUMOR | We accessed the SEER program to retrieve information about patients with primary lung tumors. There was a total of 523,941 patients with clinical data, including age, gender, race, tumor size, TNM stages, AJCC stages, overall survival (OS) time, and OS status. We excluded cases with Tis and T0 in the T stage ( | PMC10451707 |
2.2. Defining In-Hospital Mortality | lung cancer, death | LUNG CANCER | We defined in-hospital mortality in SEER as (1) OS time is ≤ 1 month after diagnosis and (2) OS status is death. Patients without OS time or OS status were excluded from the analysis. Of note, patients who passed after 1 month (OS time > 1 month) were considered to have no in-hospital mortality. Although the definition is not entirely correct because of the complexity of the clinical contexts, we believe that it describes appropriately in most cases. According to previous studies, the median length of stay of lung cancer patients who passed during the first hospital stay was 18.5 days [ | PMC10451707 |
2.3. Model Training | tumor, AJCC | REGRESSION, TUMOR | We divided the training process into 3 phases: statistical selection, information selection, and model fitting. The statistical selection phase included univariate and multivariate logistic regression analyses of interested variables with regard to in-hospital mortality. The information selection phase considered the variables with mutual information (such as tumor size, T stage, and AJCC stage) and the reliability of the variables (such as race). The final step is to fit the logistic regression model with selected features, using the default optimization algorithm. | PMC10451707 |
2.4. Model Evaluation | The model evaluation section consisted of 3 parts, (1) internal validation, (2) external validation with data imputation, and (3) sensitivity analysis. In internal validation, we performed receiver operating characteristics (ROC) analysis and bootstrap-estimated calibration in both training data and validation data. In external validation, we combined the TCGA-LUAD and TCGA-LUSC. The necessary variables in the external cohorts were used and missing values were imputed by heterogeneous incomplete variational auto-encoder (HI-VAE) ( | PMC10451707 | ||
2.5. Analysis Platform | Descriptive statistics of continuous and categorical variables were median (range) and the number of cases (percentage). We used Wilcoxon and chi-square tests to compare the difference in continuous and categorical features, respectively. The HI-VAE model was trained, using the original pipeline published by Nazabal et al. [ | PMC10451707 | ||
3. Results | PMC10451707 | |||
3.1. Patient Characteristics | We described and compared the clinical features of training ( | PMC10451707 | ||
3.2. Model Training | tumor | TUMOR | First, we listed the interested variables (predictors), including age, gender, race, tumor size, TNM stages, and AJCC stages. The first phase involved the statistical selection of these variables to build a simpler version of the model. | PMC10451707 |
3.3. Model Evaluation | In internal validation, we performed ROC analyses on training and validation data. | PMC10451707 | ||
3.4. Risk Stratification by the Model | We performed a simple K-means clustering algorithm to examine the distribution of the risk values yielded by the model. We then calculated the predictive scores of each patient in the validation ( | PMC10451707 | ||
3.5. Applications of the Model | In this section, we created 3 interfaces to use the model, including a static nomogram ( | PMC10451707 | ||
4. Discussion | NSCLC, SCLC, tumor, primary cancer, lung cancer, primary lung cancer | TUMOR, PRIMARY TUMORS, METASTASIS, SCLC, LUNG METASTASIS, DISEASE, LUNG CANCER, SAID, NSCLC, PRIMARY CANCER | The model with six fundamental variables including age, gender, tumor size, T, N, and AJCC stages which were initially built to predict the in-hospital mortality of new lung cancer cases resulted in promising applications in prognosis to enhance the quality-of-life of patients diagnosed with this challenging disease. First, in the internal validation extracted from the SEER database, both training and validation cohorts have good performances with an AUC of above 0.75 (Apart from smoking, sex is likely a risk factor to play a specific role in developing lung cancer [From the statistical standpoint, our study shows the predictive value of the training model as the probability varies from 0 to 50% of in-hospital mortality since the initial diagnosis timepoint. Having said that, Shen et al. [From the clinical standpoint, there are biases and confounding factors can be taken into account. First, in terms of diagnosis, the protocol for the differentiation of primary lung cancer from solitary lung metastasis, especially with unknown primary tumors, is challenging since the lung is considered a frequent metastatic location. Therefore, the model should be applied after the primary lung location is confirmed by careful examination. Second, the policymaking of lung cancer management varies from place to place. Because the model was built based on the SEER database, TCGA-LUAD, and TCGA-LUSC, it partly reflects the outcome of lung cancer management in developed countries. In other words, while the model is helpful to smooth the decision-making among various disease-treatment choices in advanced healthcare settings, it is likely to have less predictive value for patients in a system with fewer resources. Thus, to unveil whether the probability of in-hospital mortality of patients based in developing economies predicted less than 50% is overestimated, further study counting the finance component may need to be conducted. Furthermore, despite the fact “the higher probability, the less predictive value” phenomenon of the model cannot be denied, ultimately the main focus on end-of-life care could be the case in high-risk patients. Likewise, it appears to have an ethic-related controversy surrounding palliative care and dignified death. Hence, a cautious approach should be considered in this group in corresponding to the quality of life. Last, in spite of cutting-edge interventions related to immune-, chemo-radiotherapy, etc., lung cancer is still the leading cause of mortality [Regarding applications, we designed three platforms to put the model into practice for quantitative groundwork. The static nomogram (The study has its limitations. First, the data extracted from SEER and TCGA-LUAD, and TCGA-LUSC with different regimes made them heterogeneous. Since metastasis diagnosis has a possibility to be missed in new primary cancer diagnoses, we hope to minimize this bias by excluding the metastasis variable. However, a pilot validation in clinical may be necessary to examine the model for a comprehensive application. Second, as mentioned in the Results section, the model turned out to have a less accurate value with the probability of an in-hospital mortality rate above 50%. This limitation infers the important role of end-of-life care regardless of the survival rate. Finally, the population-based design of the study without subtype classification of NSCLC and SCLC missed the molecular insight reasoning for immunotherapeutic that has played a game changer for the survival rate improvement in recent decades, especially in countries with advanced healthcare systems. Thus, to figure out how the high- and low-risk patient discrimination are correlated to the subtypes of lung cancer like NSCLC and SCLC, future studies can possibly include that variable for an optimal model. | PMC10451707 |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10451707 | ||
Author Contributions | Conceptualization, Q.N.N.T.; M.-K.L.; T.K.; T.M.; Methodology, Q.N.N.T.; M.-K.L.; Software, M.-K.L.; Validation, M.-K.L.; Formal analysis, M.-K.L.; Investigation, Q.N.N.T.; Resources, Q.N.N.T.; Writing—original draft, Que N.N. Tran; Writing—review & editing, M.-K.L.; T.K.; and T.M.; Supervision, T.K.; T.M.; Project administration, T.M. All authors have read and agreed to the published version of the manuscript. | PMC10451707 | ||
Institutional Review Board Statement | Not applicable. | PMC10451707 | ||
Informed Consent Statement | Not applicable. | PMC10451707 | ||
Data Availability Statement | TCGA, Cancer | CANCER | The datasets generated and analyzed during the current study are available in the Surveillance, Epidemiology, and End Results (SEER) and The Cancer Genome Atlas (TCGA), | PMC10451707 |
Conflicts of Interest | The authors declare no conflict of interest. | PMC10451707 | ||
Introduction | goal-directed behavior | SECONDARY, CORTEX | Non-invasive brain stimulation (NIBS) probing the dorsolateral prefrontal cortex (DLPFC) has been shown to have little effect on working memory. The variability of NIBS responses might be explained by inter-subject brain anatomical variability. We investigated whether baseline cortical brain thickness of regions of interest was associated with working memory performance after NIBS by performing a secondary analysis of previously published research. Structural magnetic resonance imaging data were analyzed from healthy subjects who received transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), and placebo. Twenty-two participants were randomly assigned to receive all the interventions in a random order. The working memory task was conducted after the end of each NIBS session. Regions of interest were the bilateral DLPFC, medial prefrontal cortex, and posterior cingulate cortex. Overall, 66 NIBS sessions were performed. Findings revealed a negative significant association between cortical thickness of the bilateral dorsolateral prefrontal cortex and reaction time for both tDCS (left: P=0.045, right: P=0.037) and iTBS (left: P=0.007, right: P=0.007) compared to placebo. A significant positive association was found for iTBS and posterior cingulate cortex (P=0.03). No association was found for accuracy. Our findings provide the first evidence that individual cortical thickness of healthy subjects might be associated with working memory performance following different NIBS interventions. Therefore, cortical thickness could explain - to some extent - the heterogeneous effects of NIBS probing the DLPFC.Working memory is a cognitive system that allows the temporary storage and online manipulation of information that enables goal-directed behavior (Since the DLPFC is easily reached compared to deeper cortical regions, a large number of studies using non-invasive brain stimulation (NIBS) interventions, especially transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), have probed this area to modulate working memory in both healthy and neuropsychiatric participants (Heterogeneous effects of NIBS on the DLPFC on working memory performance might be explained by a variability of NIBS parameters and also by individual differences, such as anatomical variability (Therefore, based on our prior research ( | PMC10591489 |
Material and Methods | This study was based on data from a previous trial that measured working memory performance of healthy subjects after a course of NIBS protocols. The original study used a factorial, double-blinded, within-subjects design, in which participants were allocated to receive four different NIBS interventions (tDCS, iTBS, combined tDCS+iTBS, and placebo) on different days, in a randomized order ( | PMC10591489 | ||
Participants | In our previous study ( | PMC10591489 | ||
Procedure | First, an anatomical T1-weighted imaging of the brain was performed using a 3T magnetic resonance imaging (MRI) scanner (General Electric PET/MRI equipment, USA), followed by a real-time MRI-guided neuro-navigation system (Brainsight, Rogue Resolutions, Inc., Canada) using the T1-weighted image to target the left and right DLPFCs (MNI152 stereotaxic coordinates, -38, +44, +26 and +38, +44, +26, respectively) ( | PMC10591489 | ||
Back task | The 2-back task was programmed in E-prime 2.0 software (Psychology Software, Tools Inc., USA). The visual stimulus consisted of letters (A to Z) that appeared in a pseudo-randomized order on a computer screen of 15 inches. The applied protocol consisted of three blocks of 30 letters. Letters were displayed on the screen for 500 ms, with an interval of 3000 ms between displays. Each block consisted of 10 ‘target' letters, representing a total of 30 ‘targets'. Targets were letters identical to the ones presented two steps earlier in the trial sequence. Participants were instructed to press different keys on the keyboard for target (key ‘2') and non-target (key ‘0') stimuli. A brief practice containing 20 stimuli was conducted prior to the task. The 2-back task was chosen because it was previously associated with working memory improvement after NIBS in healthy participants ( | PMC10591489 | ||
NIBS protocols | Based on previous studies investigating cognitive performance after tDCS in healthy volunteers (iTBS protocol used a TMS coil applied with an angle of 45 degrees relative to the midline. The protocol consisted of 54 cycles of 10 triplet bursts with a train duration of 2 s and an interval of 8 s between trains (1620 pulses) at 110% of the resting motor threshold. The protocol lasted 8 min and 40 s. The coil B65 Active/Placebo MagVenture (Denmark) was used for both active and placebo protocols, as it has two identical sides for delivering active or placebo stimulation depending on the randomized codes imputed on the device ( | PMC10591489 | ||
MRI acquisition | All structural brain MRIs were acquired in a 3-Tesla MR system (General Electric PET/MRI equipment, USA). Volumetric images were based on T1-weighted sequences using a 3D fast-field echo pulse sequence with the following parameters: field of view (FOV) of 25.6, time of repetition (TR) of 7.7 ms, time of echo (TE) of 3.1 ms, and 202 slices. | PMC10591489 | ||
Neuroimaging processing and cortical thickness quantification | The T1-weighted image of each participant was processed using the CAT12 toolbox (In the RBM step, the Destrieux atlas (According to our | PMC10591489 | ||
Brain regions of interest investigated in this study. PCC: posterior cingulate cortex; DLPFC: dorsolateral prefrontal cortex; mPFC: medial prefrontal cortex. | PMC10591489 | |||
Statistical analysis | Statistical analyses were performed using R version 4.1.2 (USA). Reaction time (in milliseconds (ms)) and accuracy (binary outcome) of the target stimuli were the dependent variables, while ROI thickness and protocol were the independent variables. Missed responses were considered errors, and reaction times <200 ms and >2500 ms were not considered genuine responses and were excluded (Secondly, as a supplementary analysis, we investigated the association between the working memory performance after the combined protocol only and cortical thickness using the same GLMM structures described above.All results were considered significant at a P threshold of 0.05. As the analyzed brain regions were hypothesis-driven, we did correct for multiple testing, similar to what was done previously ( | PMC10591489 | ||
Results | Our prior study included a sample of 24 healthy subjects, two of which were excluded because the T1-image of one subject did not pass the quality check and one subject did not receive the placebo stimulation. Therefore, 22 subjects were included in this study, presenting a mean age of 28.4 years (SD=7.1 years), mean education of 17 years (SD=3 years), and 77% were women. All the 22 participants underwent sessions of tDCS, iTBS, and placebo in a randomized order, with a total of 66 NIBS sessions being performed. Working memory performance per condition can be found in Supplementary Table S1. | PMC10591489 | ||
Working memory and ROI thickness | First, we evaluated whether there was an association between working memory performance in the placebo group and cortical thickness, but no significant association was found ( | PMC10591489 | ||
Association of working memory performance and cortical thickness in the placebo group. | REGRESSION | For each region of interest (ROI), a generalized linear mixed models (GLMM) with an inverse-Gaussian error distribution and an inverse link function (same parameters as for main analyses) was set up with reaction time as outcome variable, and a logistic regression was performed with accuracy as the outcome variable. ROI and session were included as fixed effects and subject as a random intercept. The statistical parameters are Therefore, we investigated the association between working memory performance after iTBS and tDCS compared to placebo and cortical thickness differences. Regarding reaction time, results revealed an inverse association between working memory performance following iTBS and tDCS ( | PMC10591489 | |
Association between cortical thicknesses of regions of interest in the brain and working memory performance. | Statistics: *P<0.05 and **P<0.01; | PMC10591489 | ||
Association between baseline cortical thickness and working memory reaction time following non-invasive brain stimulation protocols. TBS: theta-burst stimulation; tDCS: direct current stimulation. | No significant association between accuracy and ROI thickness was found (The results from the association between cortical thickness and working memory performance after the combined protocol can be found in Supplementary Table S3. | PMC10591489 | ||
Discussion | In this study, based on data from our previous trial (As expected, our results showed that inter-individual anatomical differences were associated with NIBS effects. The findings revealed that subjects with thinner DLPFC regions showed relatively faster reaction times than individuals with greater cortical thickness after tDCS and iTBS interventions compared to placebo, whereas the PCC, which was the deepest area investigated, presented a positive association between its left portion and reaction time performance after iTBS.Interestingly, in our first study (The inverse association between cortical thickness and working memory performance was already reported in previous studies using interventions other than NIBS. For instance, a recent trial investigated the changes in cortical thickness of healthy volunteers after two months of working memory training and found that some structural changes were negatively associated with cognitive performance, demonstrating that larger thickness reductions led to larger training-related behavioral improvements (Our results also showed that iTBS performance, but not tDCS, presented an association with the PCC, the deepest cortical thickness region investigated. As tDCS delivers a weaker electric current compared to iTBS and does not produce action potentials per se, we hypothesized that tDCS effects may have not been robust enough to modulate inner cortical structures compared to placebo, whereas iTBS might have been able to reach the PCC after only one active session. Based on these findings, we can assume that the PCC plays an important role in working memory processes and that iTBS mechanisms of action on the left DLPFC are associated with network-level efforts.Moreover, we were not able to find an association between individual cortical thickness of the mPFC and working memory performance. Although preliminary studies suggest that bilateral tDCS montages over the DLPFC can induce stronger electric fields in the medial part of the PFC (Although our results provide the first evidence of the association between individual cortical thickness differences and working memory performance following an NIBS intervention, previous studies already suggested that brain anatomy might have an influence on NIBS response. For instance, a recent study showed that individual gray matter volume of the left DLPFC might be associated with tDCS antidepressant effects ( | PMC10591489 | ||
Limitations | Our study has several limitations that should be discussed. First, the sample size was small. Thus, some analyses might have been underpowered, and future studies should use these results as hypothesis-driven. Second, other anatomical measures such as cortical volume could have been used for this study. However, as a previous study suggests that cortical thickness could be associated with tDCS response, and other studies with elderly show that cortical thickness is more sensitive to investigate response confounders (i.e., age and sex) ( | PMC10591489 | ||
Conclusion | This study provided initial evidence that individual differences in baseline cortical thickness of the DLPFCs targeted with tDCS and iTBS and deeper regions targeted with iTBS might be associated with reaction time performance. However, no association was found between accuracy and cortical thickness. The findings of our study can be useful to guide future studies investigating individual predictors of tDCS and iTBS probing the DLPFC for working memory performance. | PMC10591489 | ||
Acknowledgments | This research project was supported by the São Paulo Research Foundation (FAPESP, Grant: 2018/10861-7). A.R. Brunoni receives grants from the National Council for Scientific and Technological Development (PQ-1B) and FAPESP (Grants: 2018/10861-7 and 2019/06009-6). A.R. Brunoni has a small equity of Flow™, whose devices were not used in the present study. The LIM-27 Laboratory receives grants from the Associação Beneficente Alzira Denise Hertzog da Silva. M.A. Vanderhasselt receives funding from the Research Foundation Flanders (FWO) and from the Ghent University (Grants: G0F4619N and BOF17/STA/030, respectively). L.B. Razza was supported by FAPESP (Grant: 2019/07256-7) and is currently supported by an FWO grant (G0F4619N). M.S. Luethi and P.H.R. da Silva are supported by FAPESP (Grant numbers: 2021/10574-0 and 2022/03266-0, respectively).Click here to view [ | PMC10591489 | ||
References | PMC10591489 | |||
BACKGROUND: | stroke, patent foramen ovale | STROKE | Right to left shunt (RLS), including patent foramen ovale, is a recognized risk factor for stroke. RLS/patent foramen ovale diagnosis is made by transthoracic echocardiography (TTE), which is insensitive, transesophageal echocardiography, which is invasive, and transcranial Doppler (TCD), which is noninvasive and accurate but scarce. | PMC10589435 |
METHODS: | RLS, embolic cerebrovascular ischemia | EVENT | We conducted a prospective, single-arm device clinical trial of robot-assisted TCD (raTCD) versus TTE for RLS diagnosis at 6 clinical sites in patients who presented with an event suspicious for embolic cerebrovascular ischemia from October 6, 2020 to October 20, 2021. raTCD was performed with standard TCD bubble study technique. TTE bubble study was performed per local standards. The primary outcome was rate of RLS detection by raTCD versus TTE. | PMC10589435 |
RESULTS: | RLS, ischemic stroke | EVENTS, TRANSIENT ISCHEMIC ATTACK, ISCHEMIC STROKE | A total of 154 patients were enrolled, 129 evaluable (intent to scan) and 121 subjects had complete data per protocol. In the intent to scan cohort, mean age was 60±15 years, 47% were women, and all qualifying events were diagnosed as ischemic stroke or transient ischemic attack. raTCD was positive for RLS in 82 subjects (64%) and TTE was positive in 26 (20%; absolute difference 43.4% [95% CI, 35.2%–52.0%]; | PMC10589435 |
CONCLUSIONS: | RLS, patent foramen ovale | raTCD was safe and ≈3 times more likely to diagnose RLS than TTE. TTE completely missed or underdiagnosed two thirds of large shunts diagnosed by raTCD. The raTCD device, used by health professionals with no prior TCD training, may allow providers to achieve the known sensitivity of TCD for RLS and patent foramen ovale detection without the need for an experienced operator to perform the test. Pending confirmatory studies, TCD appears to be the superior screen for RLS compared with TTE (funded by NeuraSignal). | PMC10589435 | |
METHODS | PMC10589435 | |||
Trial Oversight and Funding | HEART | This study comports with the Transparency and Openness Promotion Guidelines for authors publishing in the American Heart Association Journal, and the data sets can be made available by reasonable request to the corresponding author.The study was a multicenter (conducted within 6 clinical sites), prospective, single-arm, nonsignificant risk, consecutively enrolled diagnostic yield device clinical trial. The trial was run between October 6, 2020 and October 21, 2021. Specific details about methodology, including prespecified outcomes, were published previously. | PMC10589435 | |
Patients | embolic acute, embolic stroke, ischemic stroke | TRANSIENT ISCHEMIC ATTACK, EMBOLIC STROKE, ISCHEMIC STROKE | The trial included adult (≥18 years) patients who experienced a clinical episode that, in the opinion of the treatment team, included an embolic acute neurovascular episode (eg, ischemic stroke or transient ischemic attack) on the differential diagnosis prompting patient referral for a TTE with agitated saline bubble contrast as part of routine clinical care. Specific subject inclusion and exclusion criteria are included below.Subjects met all the following inclusion criteria to be enrolled in the study:18 years of age or olderPresentation with a clinical condition characterized by neurological signs and symptoms that, in the opinion of the investigator, include embolic stroke or transient ischemic attack in the differential diagnosisScheduled for TTE study with agitated saline contrast (bubble study) within ±30 days of informed consentAbility to successfully perform a Valsalva maneuver.Signed informed consentAbility to comply with the protocolSubjects were not enrolled in the study if any of the exclusion criteria were met:History of RLS/PFO closurePregnancy or lactation at the time of studyHistory of partial or full craniotomy/craniectomy within the past 6 monthsPresence of a physical limitation preventing TCD/Headmount placement | PMC10589435 |
Trial Procedures | RLS | Enrolled patients underwent raTCD (NovaGuide Intelligent Ultrasound, NeuraSignal Inc, Los Angeles, CA) in addition to standard of care TTE with agitated saline contrast bubble study, both within 30 days of informed consent. The raTCD is a five-degree-of-freedom robotic unit paired with a signal optimization algorithm that supports traditional 2 MHz diagnostic TCD. Any other diagnostics for RLS testing (eg, TEE or TCD) were optional, performed only at the discretion of the treatment team. A clinical research coordinator performed the raTCD procedure. The research coordinators had no prior TCD experience before being trained to perform standard TCD bubble study technique | PMC10589435 | |
Outcomes | RLS | ADVERSE EVENTS, SECONDARY | The primary outcome was rate of RLS detection with TTE and raTCD in the intent to scan (ITS) cohort, which included site assessment of TTE (eg, local clinical interpretation). The primary safety outcome was any serious device-related adverse events. The key prespecified secondary outcome was rate of detection of large RLS on TTE and raTCD. The other prespecified secondary outcomes, including rate of absence of transtemporal windows and device performance parameters, are in the | PMC10589435 |
Statistical Analysis | The study was powered based on the results of a meta-analysis | PMC10589435 | ||
RESULTS | PMC10589435 | |||
Outcomes | RLS | SECONDARY | For the primary outcome, in the ITS cohort, raTCD detected any RLS in 82 patients (64%) whereas TTE documented any RLS in 26 (20%) patients (absolute difference 43.4% [95% CI, 35.2%–52.0%]; OutcomesFor the secondary prespecified outcome of large RLS detection, raTCD detected large RLS in 35 patients (27%) and TTE found large RLS in 13 (10%; absolute difference 17.0% [95% CI, 11.5%–24.5%]; There were few TCD and TEE data, which were optional diagnostics in this study. Overall, there were 14 cases with TEE (11%) and 6 of those also had evaluable TCD (5%) for cross-comparison (Table Outcomes in Subjects With TEERLS% Detection raTCD Versus TEE and TCD | PMC10589435 |
Safety | anxiety | ADVERSE EVENTS | There were no serious adverse events in this study related to the device or microbubble contrast injection. There were 2 nonserious adverse events (anxiety) in the ITS population. | PMC10589435 |
ARTICLE INFORMATION | PMC10589435 | |||
Sources of Funding | This work was funded by NeuraSignal, Inc. | PMC10589435 | ||
Disclosures | Drs Alexandrov, Rubin, Tsivgoulis, and Volpi have received payment as consultants to the study sponsor. C. Douville has received travel support from the study sponsor. The other authors report no conflicts. | PMC10589435 | ||
Supplemental Material | Trial ProtocolStatistical Analysis PlanSupplemental AppendixInvestigatorsSupplemental MethodsTables S1–S4Figure S1Video S1STARD ChecklistCONSORT Checklist | PMC10589435 | ||
Supplementary Material | PMC10589435 | |||
Nonstandard Abbreviations and Acronyms | intent to scanpatent foramen ovaleright to left shuntrobot-assisted transcranial Dopplertranscranial Dopplertransesophageal echocardiographytransthoracic echocardiographyFor Sources of Funding and Disclosures, see page 2848.The podcast and transcript are available at Supplemental Material is available at | PMC10589435 | ||
REFERENCES | PMC10589435 | |||
Introduction | cardiovascular death, fracture, pain, PD, osteoporosis, Osteoporosis, systemic skeletal disease, arthralgia | MYOCARDIAL INFARCTION, STROKE, ADVERSE EVENTS, FRAGILITY, POSTMENOPAUSAL OSTEOPOROSIS, OSTEOPOROSIS, EVENTS, OSTEOPOROSIS | Edited by: Kok Yong Chin, National University of Malaysia, MalaysiaReviewed by: John Krege, Eli Lilly, United States; Jan Josef Stepan, Charles University, Czechia†These authors have contributed equally to this work and share first authorshipThis article was submitted to Bone Research, a section of the journal Frontiers in EndocrinologySHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50–400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned. Twenty-one received placebo and eighty-four received SHR-1222 sequentially (100 mg QM, n=4; 200 or 300 mg QM, n=20; and 400 or 600 mg Q2M, n=20). The most common adverse events included increased blood parathyroid hormone, increased low-density lipoprotein, increased blood alkaline phosphatase, increased blood cholesterol, back pain, and arthralgia, the majority of which were mild in severity without noticeable safety concerns. Serum SHR-1222 exposure (COsteoporosis is defined as a progressive systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture by the NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy (Medications used to treat osteoporosis are classified as either antiresorptive or anabolic in action (Mechanistically, as a negative regulator of the Wnt signaling pathway, sclerostin binds low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptors, further inhibiting bone formation and promoting bone resorption (Romosozumab is the only humanized therapeutic antibody against sclerostin that has been authorized for use in the United States, the European Union, Japan, Korea, and Canada. However, a safety warning for romosozumab for the risk of cardiovascular (CV) events (myocardial infarction, stroke, and cardiovascular death) should be noted (SHR-1222 is a novel humanized monoclonal antibody targeting sclerostin that was developed for the treatment of osteoporosis. Preclinical studies have demonstrated that SHR-1222 exhibits high affinity for human sclerostin (data on file, Jiangsu Hengrui Pharmaceuticals). Moreover, our first-in-human clinical trial (NCT03870100) indicated that single doses of SHR-1222 ranging 50–400 mg were generally well tolerated and promoted bone formation, inhibited bone resorption, and increased BMD in healthy men and postmenopausal women with low bone mass ( | PMC10116854 |
Methods | PMC10116854 | |||
Study design | This was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial of SHR-1222 in women with POP conducted at 11 sites in China (NCT04435158). Subject participation consisted of a 30-d screening period, 24-week treatment period, and 57-d treatment-free follow-up period.The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice Guidelines as well as local regulatory requirements. The study protocol and amendments were approved by the ethics committees of all participating centers, and all subjects provided written informed consent before enrolment. This study was registered with ClinicalTrials.gov (NCT04435158). | PMC10116854 | ||
Study participants | fracture, amenorrhea, hypercalcemia, fractures, Osteoporosis, osteoporosis, diabetes | INTRAVENOUS BISPHOSPHONATES, HYPERCALCEMIA, METABOLIC DISEASES, OSTEOPOROSIS, OSTEOPOROSIS, VITAMIN D DEFICIENCY, HYPOCALCEMIA, METABOLIC BONE DISEASES, DIABETES | Eligible subjects were ambulatory women of postmenopausal status for at least 5 years, aged 50–70 years, with evidence of osteoporosis and body weight of no less than 40 kg. Postmenopausal status was defined as having ≥ 12 months of spontaneous amenorrhea or undergoing bilateral oophorectomy 6 weeks prior. Osteoporosis was defined as a BMD T-score ≤ -2.5 at the lumbar spine (L1–L4, one or more vertebrae), total hip, or femoral neck using the Asian normative database integrated with the Hologic dual energy X-ray absorptiometry (DXA) scanner. The subjects had to have at least two vertebrae in the L1–L4 region and at least one hip that could be evaluated using dual-energy X-ray absorptiometry. Key exclusion criteria included a history of hip fracture, any severe or more than two moderate vertebral fractures, a history of metabolic bone diseases (except for osteoporosis) or endocrine and metabolic diseases that may disturb bone metabolism, a T-score < -3.5, at lumbar spines (L1–L4, one or more vertebrae), total hip or femoral neck, vitamin D deficiency (25-hydroxyvitamin D [25-OHD] concentration < 20 ng/mL), diabetes inadequately controlled on diet and exercise (fasting plasma glucose ≥ 7.0 mmol/L or hemoglobin A1c ≥ 7.0%), and hypercalcemia or hypocalcemia. The use of the following agents was not allowed: intravenous bisphosphonates or denosumab at any time, oral bisphosphonates, PTH or its analogs, strontium or fluoride within the previous 12 months, long-acting estrogen/progesterone replacement therapy within the previous 6 months, systemic glucocorticoids, estrogen/progesterone replacement therapy, anabolic steroids, selective estrogen-receptor modulators, calcitonin, calcitriol and its analogs, and thiazide diuretics within the previous 3 months. | PMC10116854 |
Treatment interventions | Women with POP received SHR-1222 or a matching placebo subcutaneously at doses of 100, 200, or 300 mg once monthly (QM) and 400 or 600 mg once every 2 months (Q2M) sequentially (Study design. The decision to proceed to the next dosing cohort was made by the safety review committee (SRC) consisting of sponsor representatives and investigators after all subjects in the previous cohort received the study treatment and had been monitored for no less than 36 days after dosing. Treatment was administered to each cohort for a total of 24 weeks (six doses for QM groups or three doses for Q2M groups).For subjects whose baseline serum 25-OHD level was 20–30 ng/mL, a loading dose of 400,000 IU of vitamin D was administered at baseline. All subjects were given daily calcium (500–600 mg) and vitamin D | PMC10116854 | ||
Endpoints and assessments | EVENTS, SECONDARY, BLOOD | The primary endpoint of this trial was the assessment of the safety and tolerability of multiple subcutaneous injections of SHR-1222. The secondary endpoints included PKs, PDs, and the immunogenicity of SHR-1222.Adverse events (AEs), coded according to the preferred terms of the Medical Dictionary for Regulatory Activities v25.0, were monitored and recorded. Clinical laboratory evaluations, vital signs, and 12-lead electrocardiograms were conducted for safety assessments.Blood samples for PKs and PDs were collected in the morning after an overnight fast for at least 10 hours at 19 time points: days 1, 3, 7, 15, 22, 29, 57, 85, 113, 141 (at predose if dosing); the day after the last dose of the study treatment for 2, 4, 6, 14, or 21 d (days 115, 117, 119, 127, 134 for Q2M cohorts; days 143, 145, 147, 155, and 162 for QM cohorts); and days 169, 197, and 225. PK analyses were performed at Shanghai InnoStar Bio-tech Co., Ltd., including area under the curve from time 0 to the last measurable concentration (AUCAll subjects underwent lumbar spine (L1–L4) and hip (total hip and femoral neck) DXA scans for BMD measurements during the screening period, and on days 57, 85, 169, 197, and 225, using the same Hologic Discovery Wi Bone Densitometer (Hologic, Bedford, MA, United States) at each center. Instrument quality controls were produced to ensure the coefficient of variation (CV) under 1.5% throughout the study to ensure the accuracy of the results.Blood samples for anti-SHR-1222 antibody determination were collected on days 1, 7, 29, 57, 85, 113, 141 (at pre-dose if dosing), 6 d after the last dose of study treatment (days 119 and 147 for Q2M and QM cohorts, respectively), and on day 225. Anti-SHR-1222 antibody was detected at Shanghai InnoStar Bio-tech Co., Ltd. using a validated Meso Scale Discovery electrochemiluminescence immunoassay. Blood samples were stored or transported at ultra-low temperatures ranging from -100°C to -60°C and analyzed in batches. | PMC10116854 | |
Statistical analysis | PD | All subjects who received placebo were included in the placebo group. Safety was assessed in all subjects who received at least one dose of SHR-1222 or a placebo. PK concentration and parameter analyses were performed in subjects who received at least one dose of SHR-1222, with at least one qualified PK concentration/parameter result. PD indicators were analyzed in those who received at least one dose of SHR-1222 or a placebo, with no missing baseline and at least one qualified post-baseline PD assessment data. Immunogenicity was assessed in patients who received at least one dose of SHR-1222 or a placebo, with baseline and at least one post-baseline qualified sample.The sample size was estimated based on the percentage changes from baseline to the 6Serum SHR-1222 concentration-time data were analyzed using non-compartmental methods. Baseline demographics, safety results, and PK parameters by treatment and dose were tabulated and summarized using descriptive statistics. At every scheduled visit, the percentage changes from the baseline for selected PD parameters and BMD were calculated. All statistical analyses were performed using SAS, version 9.4 (SAS Institute, Inc.). | PMC10116854 | |
Results | PMC10116854 | |||
Study participants | Between September 23, 2020, and November 29, 2021, 107 subjects who were eligible underwent randomization to receive different dosing regimens of SHR-1222 or matching placebo. Two subjects in the placebo group, who did not receive the assigned treatment, withdrew from the study. Of the 105 subjects, 21 received placebo and 84 received SHR-1222 (100 mg QM, n=4; 200 mg QM, 300 mg QM, 400 mg Q2M or 600 mg Q2M, n=20 each). Ninety-nine subjects completed the preplanned treatment period, and six stopped early (four due to subject withdrawal [200 mg QM, n=2; 300 mg QM, n=1; and 400 mg Q2M, n=1], one due to consent withdrawal in the 600 mg Q2M group, and one due to other reasons in the 300 mg Q2M group).The baseline demographics and clinical characteristics were similar between the placebo and SHR-1222 treatment groups (Demographics and baseline characteristics.eGFR was calculated using the modified MDRD formula for Chinese: eGFR (ml/min1.73mQM, once every month; Q2M, once every 2 months; SD, standard deviation; BMI, body-mass index; BMD, bone mineral density. P1NP, N-terminal propeptide of type 1 procollagen; BSAP, bone-specific alkaline phosphatase; OST, osteocalcin; β-CTx, β-C-telopeptide; Scr, serum creatinine; eGFR, estimated glomerular filtration rate; 25-OHD, 25-hydroxyvitamin D. | PMC10116854 | ||
Safety | cardiovascular and cerebrovascular ischemic | HYPOPHOSPHATEMIA, ADVERSE EVENTS, ADVERSE EVENT, SYSTEMIC ALLERGIC REACTION, ADVERSE EVENT, ANAPHYLACTIC SHOCK, EVENTS, HYPOCALCEMIA, INJECTION SITE HEMORRHAGE, LACUNAR INFARCTION | A total of 100 subjects experienced at least one AE, including 81 (96.4%) in the SHR-1222 group and 19 (90.5%) in the placebo group (Adverse events in the safety set.AEs occurring more frequently in the SHR-1222 group with a difference of ≥5% versus pooled placebo.AEs were also predefined as AESI.AE, adverse event; QM, once every month; Q2M, once every 2 months; AESI, adverse event of special interest.Systemic allergic reactions (such as anaphylactic shock), local reactions at the injection site, decreased blood calcium, decreased blood phosphorus, increased blood triglycerides, increased blood cholesterol, and cardiovascular and cerebrovascular ischemic events were prespecified adverse events of special interest (AESIs). Injection site hemorrhage was reported in 3 (3.6%) subjects in the SHR-1222 group and none in the placebo group. Calcium and phosphate metabolic disorders were found in only 4 subjects who received SHR-1222 (decreased blood calcium, 2.4% [n=2]; hypocalcemia, 1.2% [n=1]; decreased blood phosphorus, 1.2% [n=1]; hypophosphatemia, 1.2% [n=1]), but not in the placebo group. AEs of increased blood triglyceride levels occurred in 20.2% (n=17) of subjects with SHR-1222, which was similar to that reported in the placebo group (19.0%, n=4). However, increased blood cholesterol levels were reported in 10 (11.9%) subjects in the SHR-1222 group, which was higher than that observed in the placebo group (4.8%, n=1). One subject in the SHR-1222 600 mg Q2M group experienced an asymptomatic lacunar infarction, which was only noted upon imaging, and the investigator judged the causality as unrelated to the study treatment. Most AESIs are mild in severity and can be self-resolved without special medical intervention. | PMC10116854 |
PKs | TSD | The PK parameters are summarized in Pharmacokinetics of SHR-1222: noncompartmental parameter estimates.Data are median (range) for TSD, standard deviation; CV, coefficient of variation; TMean serum concentration-time profiles of SHR-1222. After a single dose of SHR-1222, the median TAfter the last dosing of SHR-1222, the median T | PMC10116854 | |
Bone turnover markers | Mean percentage changes from baseline in the levels of the bone formation markers P1NP, BSAP, and OST and bone resorption marker β-CTx are presented in Mean (SD) percentage changes from baseline in bone turnover biomarkers. After different dosing regimens of SHR-1222 in the order of 100, 200, and 300 mg QM; 400 and 600 mg Q2M, the serum levels of P1NP increased from the baseline and reached the peak on days 15–22. The maximum mean percentage increases in P1NP after the first administration were 91.4%, 136.4%, 153.7%, 144.5%, and 171.4% in the 100 mg QM, 200 mg QM, 300 mg QM, 400 mg Q2M and 600 mg Q2M SHR-1222 dosing group respectively, compared with 3.0% in the placebo group (In addition, the bone resorption marker β-CTx significantly decreased in the SHR-1222 groups compared to the placebo group for at least the initial 4 weeks. The lowest levels were reached during days 10–22 since the first administration (-44.6%, -34.7% and -38.3% for 100 mg, 200 mg and 300 mg QM group; -31.2% and -39.7% for 400 mg and 600 mg Q2M groups, respectively; compared with -16.4% for placebo) ( | PMC10116854 | ||
BMD at the lumbar spine, total hip, and femoral neck | Compared with the placebo group, significant increases from baseline in BMD were observed at the lumbar spine across all SHR-1222 dosing groups 2 months after the first administration, which continued to rise throughout the subsequent treatment (Mean (SD) percentage changes from baseline in bone mineral density (BMD). | PMC10116854 | ||
Immunogenicity | Eighty-three subjects with SHR-1222 were included in the immunogenicity analyses, among whom six (7.2%) tested positive for anti-SHR-1222 antibodies after administration (100 mg QM, n=1; 300 mg QM, n=1; 400 mg Q2M, n=1; 600 mg Q2M, n=3). However, the development of anti-SHR-1222 antibodies had no discernible effect on the main dose-standardized PK parameters (such as C | PMC10116854 | ||
Discussion | PD | This randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial is the first clinical evaluation of multiple doses of SHR-1222 for POP treatment. SHR-1222 was generally well tolerated and demonstrated an acceptable safety profile at different dosing regimens from 100 mg QM to 600 mg Q2M. The AE profile of the SHR-1222 group was comparable to that of the placebo group during the whole treatment and follow-up, except for six AEs that showed ≥ 5% higher incidences in subjects with SHR-1222 than in those with placebo. Of these, the bone-specific blood ALP level increased as expected in a dose-dependent manner, with no induction in activities of liver enzymes (such as ALT, AST, and gamma-glutamyl transferase). The increased blood ALP level may be associated with the powerful promotive effect of SHR-1222 on bone formation, which was also observed in our preclinical studies of SHR-1222 (data on file, Jiangsu Hengrui Pharmaceuticals) and is in agreement with the phase 1 trial of romosozumab (This phase 1 trial provided evidence that after multiple subcutaneous injections of SHR-1222 ranging from 100 mg QM to 600 mg Q2M, the serum exposures (CThe dose-dependent PD responses of SHR-1222 were observed in the bone turnover biomarkers P1NP, OST, BSAP, and β-CTx, suggesting that SHR-1222 simultaneously enhances bone formation and reduces bone resorption, leading to increased BMD. The peak P1NP level increased from baseline in the SHR-1222 dosing group of 200 mg QM, which was close to that reported in a Japanese population who received romosozumab 210 mg QM (Of the 83 subjects with SHR-1222 included in the immunogenicity analyses, six (7.2%) developed anti-SHR-1222 antibodies. Similar drug-related anti-drug antibodies were obtained after a single dose of SHR-1222 (10.0% of subjects) and romosozumab (11.1% of subjects) (In conclusion, in this dose-escalation phase 1 trial, multiple doses of SHR-1222 were safe and well-tolerated ranging from 100 mg QM to 600 mg Q2M. The serum SHR-1222 exposure (C | PMC10116854 | |
Data availability statement | The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author. | PMC10116854 | ||
Ethics statement | The studies involving human participants were reviewed and approved by the Ethics Committee of the Second Xiangya Hospital of Central South University and all other participating centers. The patients/participants provided their written informed consent to participate in this study. | PMC10116854 | ||
Author contributions | HC | Conceptualization: ZD, RZ, ZS, HC, and ZGZ; Data curation: ZD, RZ, ZS, GQ, XL, QQ, CLS, LL, PJ, GY, YC, DP, CZ, LW, JS, QZ, ZZ, XY, PF, QY, LY, XF, WLiu, BW, RC, XW, YX, and ZGZ; Formal analysis: WW; Supervision: ZD, RZ, ZS, HC, and ZGZ; Project administration: ZD, RZ, ZS, CS, KS, WW, WLu, HC, and ZGZ; Writing – original draft: ZD, RZ, ZS, HC, and ZGZ; Investigation: All authors; Methodology: All authors; Writing – review & editing: All authors. All authors contributed to the article and approved the submitted version. | PMC10116854 | |
Acknowledgments | This study was sponsored by Jiangsu Hengrui Pharmaceuticals Co., Ltd. We thank the subjects and their families, as well as all the investigators and research staff for participating in this study. We also acknowledge Lin Dong, PhD (a medical writer at Hengrui) for medical writing support according to Good Publication Practice Guidelines. | PMC10116854 | ||
Conflict of interest | Authors CS, KS, WW, WLu, and HC were employed by Jiangsu Hengrui Pharmaceuticals Co., Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.This study received funding from Jiangsu Hengrui Pharmaceuticals Co., Ltd. The funder had the following involvement with the study design, data collection and analysis. | PMC10116854 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10116854 | ||
References | PMC10116854 | |||
Abstract | PMC10834340 | |||
Background | LITTLE | Little research has been undertaken on the benefits of frailty management within different hospital settings. The objective of this study is to provide evidence on the viability and effectiveness of frailty management in non‐geriatric hospital settings on mortality and functional decline after discharge. | PMC10834340 | |
Methods | delirium, Frailty | REGRESSION | Data from the FRAILCLINIC (NCT02643069) study were used. FRAILCLINIC is a randomized controlled trial developed in non‐geriatric hospital inpatient settings (emergency room, cardiology and surgery) from Spain (2), Italy (2) and the United Kingdom (1). Inpatients must met frailty criteria (according to the Frailty Phenotype and/or FRAIL scale), ≥75 years old. The control group (CG) received usual care. The intervention group (IG) received comprehensive geriatric assessment (CGA) and a coordinated intervention consisting in recommendations to the treating physician about polypharmacy, delirium, falls, nutrition and physical exercise plus a discharge plan. The main outcomes included functional decline (worsening ≥5 points in Barthel Index) and mortality at 3 months. We used multivariate logistic regression models adjusted by age, gender and the Charlson index. Intention‐to‐treat (ITT) and per‐protocol (PP) analyses were used. | PMC10834340 |
Results | Eight hundred twenty one participants (IG: 416; mean age 83.00 ± 4.91; 51.44% women; CG: 405; mean age 82.46 ± 6.03; 52.35% women) were included. In the IG, 77.16% of the participants followed the geriatric team's recommendations as implemented by the treating physicians. The intervention showed a benefit on functional decline and mortality [OR: 0.67(0.47–0.96), | PMC10834340 | ||
Conclusions | An individualized intervention in frail in‐patients reduces the risk of functional deterioration and mortality at 3 months of follow‐up when a care management plan is designed and followed.
Marta Checa‐López and Alba Costa‐Grille equally contributed to this work. | PMC10834340 | ||
Background | Frailty, institutionalization reduction | SYNDROME | Population ageing and the concomitant rise in the number of frail older adults represent a serious health and social care challenge.Frailty is a geriatric syndrome characterized by a diminished capacity to respond to stressors, as a result of a reduced functional reserve.Frailty is highly prevalent among the inpatient hospital setting varying from 27% to 80%.Some evidence has demonstrated the benefits of acute care for the elderly (ACE) units in terms of functional decline and institutionalization reduction in a mid‐term.This study aims to evaluate the effectiveness of the detection of frailty and intervention on it by a geriatric consultation team in inpatients at non‐geriatric in‐hospital settings, | PMC10834340 |
Methods | PMC10834340 | |||
Trial design | cognitive impairment, fatigue, and loss of weight, Frailty, involuntary weight loss | ONCOLOGY, RECRUITMENT | FRAILCLINIC (NCT02643069) was a phase III multicentric randomized clinical trial conducted between June 2016 and March 2021. We recruited inpatients older than 75 years admitted to some of the following clinical settings: emergency room (ER), cardiology and surgery (both as an elective‐ES and urgent surgery‐US). The study was carried out in two hospitals in Spain (University Hospital of Getafe and Monte Naranco Hospital, Oviedo), two in Italy (Sacro Cuore University Hospital and San Rafael Hospital, both in Rome) and one setting in the United Kingdom (Luton & Dunstable University Hospital, that was substituted by the Aston University Hospital in the last 6 months of the trial). The settings were selected based on the availability of the centers where the study was conducted. Oncology department was also initially included, but was finally discarded in the early phases of the study due to lack of recruitment. Participants were recruited consecutively among all the patients (age > 75 years) who attended the four settings of the study. The setting of care registered in the database for every participant was the one where they were contacted for the first time by the Geriatric Team. Researchers checked every day those admissions and excluded those with data informing about exclusion criteria in the electronic clinical records. After this first selection, they met the potential participants and after obtaining their verbal acceptance to be screened, they were assessed regarding their frailty status at admission by means of two validated frailty tools: the Fried's Frailty Phenotype (FP)Very briefly, the Fried Frailty Scale assesses five domains: fatigue, involuntary weight loss, slow gait speed, low grip strength and low levels of physical activity. The FRAIL scale evaluates fatigue, resistance, ambulation, illnesses and loss of weight. Using either tool, an individual is frail if they met three or more of the five frailty criteria. Exclusion criteria were moderate to severe cognitive impairment (Mini‐Mental State Examination (MMSE)Baseline characteristics for both groups were recorded during the first 24 h after admission, including demographic and anthropometric characteristics, medical history (admission diagnosis and co‐morbidities) and medication use recorded from clinical records. Basal (1 week before admission) functional [Barthel Index (which ranges from 0 to 100, the latter the best independence score) and Lawton scale (scoring from 0 to 6, being 6 the score for an independent statusParticipants were randomized 1:1 automatically using a random number registry conducted by a blinded manager at each centre. | PMC10834340 |
Description of the intervention and control groups |
The geriatric team provided the recommendations for each patient to the treating physician by two concurrent sources: writing them in the clinical record plus explaining to him/her in person, as they were responsible for implementation of the intervention. The team was composed of by a ‘core’ team (geriatrician and nurse) plus any other professional (physiotherapist, sport science professionals, nutritionist, registered dietitians, pharmacist, occupational therapist, psychologist and social worker) needed to improve the assessment or the design of the interventions in any particular patient. Patients were visited daily during their stay to check if the recommended measures had been implanted, updating them according to the clinical evolution, and reminding the treating physician if they had not been implemented. Only those patients where all the recommendations were implemented by his or her treating physician were considered ‘compliant’.
Both groups underwent telephone follow‐up at 3 months ± 1 week after hospital discharge. The researchers who carried out this follow‐up were blinded regarding the patient's group, intervention or control. | PMC10834340 | ||
Adverse events | delirium, constipation | ADVERSE EVENTS, NOSOCOMIAL INFECTIONS, URINARY INCONTINENCE, HYPOGLYCAEMIA | Information about the following adverse events were collected: constipation, urinary incontinence, instability, falls, adverse drugs reactions, hypoglycaemia, low blood pressure (<100 mmHg of systolic blood pressure), delirium and nosocomial infections. | PMC10834340 |
Outcomes | disability | EVENT | The primary outcomes are the effects of the intervention on functional decline (assessed by the Barthel Index), institutionalization (yes/no) and mortality (yes/no) 3 months after discharge. With reference to functional decline, a worsening in Barthel score (≥5 points) regarding the basal (pre‐hospitalization) score, was considered the event. Secondary outcomes included disability in the instrumental daily life activities (assessed by the Lawton scale), visits to the ER (yes/no), hospital readmissions (yes/no) and changes in the frailty status, evaluated by the FRAIL scale. Worsening in the Lawton scale score (≥1 point) and improvement in the FRAIL scale score (≥1 item) were considered the event for the analysis.Baseline visits were performed face to face. Follow‐up visits after discharge (at 3 months ± 1 week) were carried out by telephone. In this follow‐up phone call, all the outcomes were assessed. | PMC10834340 |
Statistical analysis | EVENTS | We calculated the sample size to minimize the estimation bias. For doing so, it is recommended to have a minimum of five and seven outcome events per independent variable (intervention, age, gender and Charlson Index) (Peduzzi et al., J Clin Epidemiol 1996). This means that for a 95% confidence interval (alpha error: 0.05), we need a minimum number of 28 events. Based on these considerations, sample size was calculated using the formula
Descriptive data were shown as mean (standard deviation) and frequency (%) for continuous or categorical variables, respectively. The comparisons between groups were assessed using Mann–Whitney test and We used multivariate logistic models to assess the effect of the intervention on adverse outcomes. We used age, gender and Charlson IndexThe significance level was established at | PMC10834340 | |
Results | Frailty, constipation | ADVERSE EVENTS, SECONDARY | A total of 821 subjects were recruited with 405 being randomly assigned to the control group and 416 to the intervention group (Figure Study flow chart diagram.Clinical and functional values by treatment group.
Abbreviation: MMSE, Mini‐Mental State Examination.CAG of the participants was followed by the building of a care plan in the IG in all cases, although this was not the case for the implementation of the recommendations by the treating physician. In fact, 321 subjects within the intervention group complied with the recommendations given by the geriatric team, which represented 77.16% of that group sample, while the treating physician did not implement the care plan designed by the team in 95 (22.84%) participants.Regarding the primary outcome, the intervention showed a decrease in the risk of worsening the Barthel Index at 3 months after discharge ranging from 28% [OR (95% CI) 0.72 (0.51–1.01; Effect of intervention on the primary outcomes (odds of worsening of the Barthel index score and mortality) at 3 months per setting according to the intention‐to‐treat and per protocol analysis.
Abbreviations: Car, cardiology; CI, confidence interval; ER, emergency room; ES, elective surgery; OR, odds ratio; US, urgent surgery.According to the secondary outcomes (Table Effect of intervention on the secondary outcomes (odds of worsening of the Lawton index and FRAIL scale, re‐admissions and visits to the emergency room) at 3 months per setting according to the intention‐to‐treat and per protocol analysis.
Abbreviations: Car, cardiology; CI, confidence interval; ER, emergency room; ES, elective surgery; OR, odds ratio; US, urgent surgery.After this initial analysis, we separated our sample in order to explore the effect of the intervention on the participants depending upon the frailty tool which identified them as frail at baseline [(Frailty Phenotype or the FRAIL scale (Tables Intervention effect on the primary outcomes (odds of worsening of the Barthel index score and mortality) selecting those participants who were frail exclusively according to the frailty phenotype or the FRAIL scale.
Abbreviations: Car, cardiology; CI, confidence interval; ER, emergency room; ES, elective surgery; OR, odds ratio; US, urgent surgery.Additionally, we assessed the number needed to treat (NNT) to measure the effect of the intervention in those variables in which we found that the intervention had an impact. The estimated NNT for mortality was 44. In relation to the improvement in the Barthel and Lawton scales compared with control patients, the NNT were 19 and 13, respectively. Furthermore, the NNT to avoid a poor outcome in those same outcomes in IG than in the CG were 23 and 38, respectively.We detected 547 adverse events, 225 in 152 participants of the UCG and 322 in 209 participants of the IG. None of these adverse events were related to the intervention, nor motivated the exclusion of the study. Except for constipation (115/405 in UCG vs. 165/416 in IG; | PMC10834340 |
Discussion | death, Frailty, frailty syndrome, ’ | STRESSFUL EVENTS | The benefits of interventions on frail hospital inpatients are far to be proven.This effect was observed when the treating physician followed the recommendations of the geriatric team. It is worthy to mention that, taking into account previous reports showing a low rate of compliant by the treating physician of the recommendations of a geriatric team,A Cochrane systematic review showed that the use of CGA in older adults admitted to hospital increases the likelihood of being ‘alive and in their own homes’ from 6 weeks to 12 months of follow‐up but did not find differences when mortality was treated as the only variable in the same period of follow‐up.There is a high disparity between tools in the identification of frail patients and this fluctuates between the settings of careIn our study, the greatest benefit is shown in the ER and in Cardiology. However, the aim of the study was not to assess differences among settings and because of that the sample size (and accordingly the power to detect differences) was calculated for the whole sample. As a consequence, there is a potential for additional differences that did not reach statistical significance in our analysis due to the above mentioned reason. Moreover, the marginal statistical significance of these findings in our study makes them less reliable and, indeed, merits further confirmation in future studies.Hospitalization is one of the most stressful events for older adults,To date, dozens of tools have been used to capture the frailty syndrome,The number of those admitted to care home was lower than forecasted, and did not allow us to run any type of analysis and, accordingly, of reaching any firm conclusion about this outcome.We must mention some limitations of our study. The intervention was implemented according to the means and professionals involved in every site and the local clinical pathways available in each one of them. In addition, we have not directly approached the issue of differences between countries, which was not among the purposes of the study and for which we did not have enough statistical power. However, we must take into account that the intervention was done added, but not instead of, to the usual care provided in every hospital. This fact supports that the benefits are accounted by the intervention, although differences in local practices cannot be absolutely excluded as a potential explanation for our findings, making sensible to replicate the study in countries with different organization of their health and social services.Moreover, co‐morbidity was higher in the IG than in the CG at baseline, a fact that could interfere with the results. To tackle with this potential source of bias, we have adjusted by co‐morbidity in the analysis and, in any case, the bias should be in the opposite address, as the group with the highest co‐morbidity (and potentially poorer results) is the intervention one. Another limitation that should be mentioned is the lack of information about functional status of the participants at discharge of the participants. Taking into account that the intervention started during hospitalization and that some studies have shown that indeed short‐term interventions during hospitalization can produce benefits on functional status,Finally, we could not perform a time‐sensitive analysis of the time to death because some logistical problems prevented to get these data from the centralized records available in one of the participating countries. However, the short time of follow‐up after discharge (3 months) makes less relevant this issue.Our results have been obtained using two frailty tools stemming from the ‘Frailty Phenotype’ model. Studies involving individuals with frailty identified through other frailty scales based on the ‘deficit accumulation’ model of frailty would be important to be undertaken in the future.Some contamination cannot be excluded, as the patients allocated to the CG were managed according to usual care, including the consultation with the liaison team of the Geriatric Department on demand from the treating physician. However, this contamination would lead to an underestimation of the effect, strengthening the relevance of our results.This study has important strengths. We have enrolled a randomized controlled clinical trial with an important amount of frail older people, a total of 821 subjects from three countries, providing a high consistency to our findings. Moreover, usual high‐risk clinical settings for frail older patients were evaluated | PMC10834340 |
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