Multicenter Clinical Trial Research Articles

Prognosis of patients with liver single-organ metastases: Updated survival results of BBCAPX-II.

157 Background: Although immunotherapy has changed the treatment strategy for many cancers with great success, patients with microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) especially with liver metastases have a low response rate to immunotherapy. Sintilimab plus bevacizumab and CapeOX (BBCAPX) has proved its efficacy and safety in above unresectable mCRC patients (1). Here, we report subgroup analysis of updated survival results of this single arm, open-label, phase 2 trial. Methods: Eligible patients were histologically confirmed unresectable metastatic colorectal adenocarcinoma by multidisciplinary team, and had RAS gene mutation and confirmed MSS status. All patients received treatment with sintilimab plus bevacizumab, oxaliplatin and capecitabine of each 21-day cycle. ORR, DCR, PFS, OS, and subgroup analyses based on metastasis site were performed. Results: From April 2021 to December 2021, 25 patients were enrolled. The ORR was 84% and the DCR was 100%. Six (24%) patients including 5 patients with liver single organ metastases underwent surgical treatment and unexpectedly achieved no evidence of disease status. At the data cut-off day (September 13, 2024), patients with liver single organ metastases presented better prognosis. Median PFS was 25.3 months (95% CI, 4.8-NA) in the patients with liver single organ metastases and 11.5 months (95% CI, 4.83-24.3) in the patients with other metastasis. Median OS was not reached in the patients with liver single organ metastases and 35.5 months (95% CI, 9.36-NA) in the patients with other metastasis. The OS rate at 24 months was 72% (95% CI, 56.4-91.9) in FAS. Median OS was not reached in FAS and 35.5 months (95% CI, 11.4-NA) in PPS. 32% patients had at least one grade 3 or 4 TRAEs. No grade 5 adverse events occurred during the study. Conclusions: This study provides a highly promising regimen for patients with RAS-mutant, MSS, unresectable mCRC, especially those with liver single organ metastases. Furthermore, we are launching a phase III, randomized, open-label, multicentric clinical trial (NCT05171660) to further analyze the effects, safety, and prognostic biomarkers of this regimen. 1. Xuefeng Fang et al. ASCO 2022. Clinical trial information: NCT04194359 . PFS and OS results of BBCAPX-II study. Median PFS 6m PFS rate (%) 12m PFS rate (%) Median OS 12m OS rate (%) 24m OS rate (%) Full analysis set (FAS), n = 25 17.9 (95% CI, 8.84-27) 84 (70.8-99.7) 56 (39.6-79.3) NA 76 (61-94.7) 72 (56.4-91.9) Per-protocol set (PPS), n = 19 9.79 (95% CI, 6.44-27.9) 78.9 (62.6-99.6) 42.1 (24.9-71.3) 35.5 (95% CI, 11.4-NA) 68.4 (50.4-92.9) 63.2 (44.8-89) Classified by metastatic organs (FAS, n = 25) Liver single organ metastases, n = 10 25.3 (95% CI, 4.8-NA) 90 (73.2-100) 70 (46.7-100) NA (11.4-NA) 90 (73.2-100) 80 (58.7-100) Other metastases, n = 15 11.5 (95% CI, 4.83-24.3) 80 (62.1-100) 46.7 (27.2-80.2) 35.5 (9.36-NA) 66.7 (46.6-95.3) 66.7 (46.6-95.3)

Analysis of lipogenic and metabolic subtypes and survival outcome in patients with pancreatic adenocarcinoma.

775 Background: Delayed diagnosis and rapid progression are major drivers of poor survival outcomes for Pancreatic Ductal Adenocarcinoma (PDAC). In previous studies, molecular profiling in tumor tissue has identified Cholesterogenic, Classical, or Exocrine-Like pathological subtypes associated with improved prognosis. Herein, in a clinical trial called Project Survival, we molecularly and clinically characterized a prospective PDAC biomarker cohort. This multicenter (n=6) clinical trial (NCT 02781012) of PDAC combined with high-fidelity longitudinal phenotypic characterization and multi-omic profiling was utilized to identify biomarkers with diagnostic and therapeutic utility. The study included assessment of plasma, serum, buffy coat, urine, saliva, and tumor tissue samples and followed 269 PDAC subjects for up to 7 years (Median survival was 700 days, with IQR of 822 days). Methods: We assessed plasma samples to identify circulating biomarkers using proteomics, metabolomics, and lipidomics profiling. Multi-omic comparison of patients with Overall Survival (OS) above the 75th percentile (improved survival) against those with OS below the 25th percentile (poor survival) was performed. Results: We identified distinct panels of proteins, metabolites, and lipids that were associated with patient survival outcomes. Protein biomarkers that were increased in improved survival outcomes were associated with cholesterol metabolism (7/14, p-value = 0.00085) and glycolysis/gluconeogenesis (5/12, p-value = 0.00089), however, protein markers associated with immune surveillance and inflammation were associated with poorer survival. For metabolite biomarkers, 19 metabolites were increased in poorer survivors of which 13/19 were carnitine metabolites, and 42 metabolites were increased in patients with improved survival. Interestingly, only two lipid molecular species of the diacylglyceride family were increased in patients with poorer survival. Conclusions: Project Survival, a prospective biomarker-driven clinical trial identified distinct metabolic and molecular subtypes of patients which characterize survival outcome in PDAC. These subtypes go beyond tumor genomic characterization and align with distinct cholesterogenic and glucogenic phenotypes associated with survival outcomes, which can potentially be leveraged for therapeutic intervention strategies.

A phase 1/2 study to evaluate CHM-2101, an autologous cadherin 17 (CDH17) chimeric antigen receptor (CAR) T cell therapy for the treatment of relapsed or refractory gastrointestinal cancers.

TPS844 Background: Patients with advanced gastrointestinal (GI) malignancies have poor prognoses and limited treatment options. Cadherin 17 (CDH17) is a cell membrane-associated protein important for GI cell-cell interactions that is expressed in proximity to epithelial tight junctions. In some GI malignancies, CDH17 expression is also expressed diffusely across the cancer cell membrane, thus providing access to CDH17 directed CAR T-cells. CHM CDH17 is a third generation autologous CAR T-cell product candidate that was designed to target and eradicate CDH17+ solid tumors. Notably, expression of CDH17 varies across indications in the cancer setting CDH17– TABLE 1. Methods: Clinical Trial NCT06055439 is a seamless Phase 1/2 clinical trial of autologous CHM CDH17 CAR T-cells for patients with advanced gastric cancer (GC), colorectal (CRC) cancer or neuroendocrine tumors (NETs) of the midgut or hindgut. As CDH17 expression in GC is heterogenous, GC subjects will be screened for CDH17 expression. In preparation for receiving CDH17 CAR T-cells, subjects receive 3-days of lymphodepleting intravenous (IV) chemotherapy (fludarabine and cyclophosphamide). The Phase 1 portion of the clinical trial uses a 3+3 dose escalation and a starting dose of 50 million CAR-T cells in a single IV infusion. Decisions regarding dose escalation/de-escalation are based on real-time dose-limiting toxicity evaluation during the first 28 days of treatment during dose escalation. After establishing a recommended Phase 2 dose, three indication-specific Simon 2-Stage cohorts will be initiated in (1) GC (2) CRC and (3) NETs of the midgut or hindgut to further characterize the safety and assess the efficacy of CHM CDH17 CAR T-cells. This is an ongoing first-in-human multi-center clinical trial of CHM CDH17, a CDH17 directed autologous CAR T-cell product candidate, enrolling subjects with advanced GI cancers that express CDH17. Clinical trial information: NCT06055439 . Expression of CDH17 in selected gastrointestinal cancer indications. Indication Sample size CDH17Expression %* Colorectal cancer 821 96% Neuroendocrine tumors of the midgut and hindgut 119 97% Gastric cancer 1,409 64% *Expression of total tumors tested for CDH17 by immunohistochemistry (CHM data on file).

The STROGHAT study protocol: An intervention study to evaluate safety, effectiveness and feasibility of treating gambiense HAT seropositive subjects with acoziborole.

Background Coordinated efforts in the control of gambiense human African trypanosomiasis (gHAT) have significantly reduced its endemicity. WHO targets interruption of transmission by 2030. However, challenges remain, including low sensitivity of the current parasitological confirmation tests, leaving a potential human reservoir untreated. Acoziborole, a single-dose oral treatment, effective in both disease stages with a good safety profile, offers the potential of treatment of parasitologically negative gHAT seropositive subjects, which could improve diagnostic sensitivity. The STROGHAT study aims to evaluate whether this approach can lead to elimination of T.b. gambiense from its human reservoir, and to provide further safety data on acoziborole. It also includes a costing analysis and a prospective evaluation of the performance of the screening and diagnostic tests used. Methods STROGHAT is a one-arm epidemiological study, with a nested phase IIIb, one-arm, open label, non-randomized, multicentre clinical trial. It will be implemented over four years in the endemic region of the Equateur North, in the Democratic Republic of Congo. For the first three years, parasitologically negative gHAT seropositive subjects will be treated with acoziborole, while parasitologically confirmed cases will receive standard of care. Individual follow-up needs and accurate prevalence estimate will be based on immunological and molecular tests performed for all gHAT screening test seropositive subjects at a reference laboratory. In the fourth year, standard procedures will resume, and a prevalence survey will assess whether interruption of transmission has been achieved. Discussion The manuscript outlines the study background, objectives and methods while discussing its strengths and challenges. If successful, the STROGHAT study will provide critical evidence on the effectiveness, safety and feasibility of the new strategy, and inform future elimination strategies. Clinical trial registration NCT06356974. Date of registration: April 4, 2024.

Sex Differences in Neurological Outcome at 6 and 12 Months Following Severe Traumatic Brain Injury. An Observational Analysis of the OXY-TC Trial.

The effect of sex in outcomes after severe traumatic brain injury (TBI) remains uncertain. We explored whether outcomes differed between women and men after standardized care management during the first 5 days in the intensive care unit (ICU). This study was an observational analysis of the OXY-TC multicenter randomized clinical trial between June 15, 2016 and April 17, 2021. Recruited patients had a pre-hospital Glasgow Coma Scale (GCS) score of 3-8, mechanical ventilation, and intracranial pressure (ICP) with or without brain tissue oxygen pressure (PbtO2) monitoring. Objectives were to maintain ICP at 20 mmHg or below and PbtO2 above 20 mmHg at all times. The primary end-point was the proportion of women and men with poor outcomes at 6 months, corresponding to an extended Glasgow Outcome Scale (GOSE) score of 1-4 (death to upper severe disability). Of 318 randomized patients, 200 men and 71 women were analyzed. They were comparable in age, comorbidities, and initial injury severity scores. However, women had larger doses of ICP as the proportion of monitoring time of ICP above 20 mmHg 8% (3-18; median, interquartile range) versus 3% (1-10), respectively (p = 0.002). They required more often at least one tier-3 treatment, i.e., barbiturate coma and therapeutic hypothermia, for refractory intracranial hypertension during the first 5 days in the ICU: 33/68 (48%) versus 60/193 (31%), respectively (p = 0.012). At 6 months, the proportion of women with GOSE 1-4 was significantly higher than men: 48/71 (68%) versus 94/200 (47%), respectively (odds ratio 2.35 [1.33-4.16]; p = 0.003]. Similar differences were found using Disability Rating Scale and Functional Independence Measure at 6 and 12 months, and GOSE at 12 months. Sex differences in neurological outcomes persisted after adjustment for other determinants of outcome such as age, initial GCS score, and dose of ICP during the 5-day monitoring. In conclusion, women sustained more severe ICP and required more active treatment, both of which would explain a worse outcome after severe TBI. Prospective research is required to confirm these findings and identify possible mechanisms. Trial registration: ClinicalTrials.gov Identifier NCT02754063 (April 28, 2016).

Trends in Colorectal Cancer Peritoneal Metastases Research: A Comprehensive Bibliometric Analysis.

Colorectal cancer (CRC) stands as the third most prevalent malignancy globally and is recognized as the second leading cause of cancer-related mortality. Notably, nearly 50% of individuals diagnosed with CRC ultimately develop metastatic disease, with the peritoneum emerging as the second most frequent site for metastatic spread. Recent advancements in therapeutic frameworks have enhanced both survival rates and quality of life metrics for patients afflicted with colorectal cancer peritoneal metastases (CRCPM). This study endeavors to facilitate an in-depth review of the current scientific landscape surrounding CRCPM, ultimately aiming to delineate future avenues for investigative research in this realm. Employing R software through the Bibliometrix package, alongside analytical tools such as CiteSpace and VOSviewer, we performed a comprehensive bibliometric analysis. This enabled us to assess pivotal keywords, prominent authors, influential countries, notable institutions, relevant literature, and key journals pertinent to the field of CRCPM research. Our findings illustrate a significant uptick in the volume of publications addressing CRCPM, with the USA leading in overall contribution, complemented by substantial input from distinguished scholars in the Netherlands and France. The author Ignace H. J. T. de Hingh emerged as the most prolific contributor. Current research endeavors have predominantly focused on the characterization of primary malignancies with peritoneal metastases, therapeutic interventions for CRCPM, and the orchestration of clinical trials. This analysis culminates in a systematic encapsulation of the prevailing research findings concerning CRCPM, underscoring current hotspots and predicting future trends within the global research spectrum. The exploration of treatment modalities for CRCPM remains vibrant, and ongoing multicenter clinical trials are anticipated to further enrich our understanding and management of this challenging clinical issue.

P0254 Cost of telemonitoring with the App TECCU in Inflammatory Bowel Disease compared to standard care in Spain: a multicenter clinical trial of GETECCU

Abstract Background Data of telemonitoring costs in inflammatory bowel disease (IBD) are scarce and restricted to a few centres. We evaluated healthcare and indirect costs of telemonitoring of IBD compared to standard care after 52 weeks on a nationwide scale. Methods A 2-arm randomized multicenter study was performed in 24 Spanish centers. We included adult patients with IBD who initiated therapy with immunosuppressant or biological agents. Patients with ileorectal/ileo-pouch anal anastomosis, stoma, active perianal disease or no Internet access were excluded. The follow-up in the telemonitoring group (G_TECCU) was based on the use of the TECCU app, while in the control group (G_control) it was based on in-person visits and telephone calls as per usual practice. We compared the number and cost of remote and in-person visits, as well as the cost of the patient trips to the medical center including the distance, time lost from work and monetary expenses1. Continuous variables are presented as mean and standard deviation (SD) and qualitative variables as absolute and relative frequency (%). Results We included 159 patients, and 126 of them completed the 52-week follow-up. The demographic and clinical variables are listed in Table 1. The mean of contacts per patient (in-person + remote) was 6.9 (1.9) in G_TECCU and 7.0 (1.9) in G_control (p=0.741). TECCU shifted in-person visits (3.1 (0.8) in G_TECCU vs 4.8 (1.5) in G_control, p=0.001) to remote contacts (3.7 (1.5) in G_TECCU vs 2.3 (1.0) in G_control, p=0.001). Non-scheduled visits were done in 63 (10.9%) patients (0.8 visits/patient) in G_TECCU compared to 50 (7.8%) patients (0.6 visits/patient) in G_control (p=0.538). These differences (Table 2) resulted in mean direct expenses of 130.6 (34.8) vs 225.3 (61.0) euros in G_TECCU vs G_control (p=0.001), being 124.3 (33.9) vs 192.5 (58.1) euros/patient for in-person visits (p=0.001) and 6.3 (2.5) vs 34.1 (15.6) euros/patient for remote contacts (p=0.001). The mean patient round-trip expenses for visits were 17.25 (27.3) euros in G_TECCU and 38.80 (47.2) euros in G_control (p=0.001). Patients from G_TECCU made a mean of 69.04 (121.3) Km and they lost a mean of 38.65 (37.7) % of their working hours during in-person visits, compared to 175.40 (217.9) Km and a mean of 45.48 (39.1)% of their working hours in G_control (p (Km)=0.001, and p (work)=0.265). According to the number of visits performed and their costs, each patient in G_TECCU saved 52.27 (79.3) Km of distance, 12.56 (8.2) hours in time out of work and 12.63 (15.9) euros in round-trip journeys. Conclusion Telemonitoring through the TECCU app reduces the number of in-person visits, the time out of work and monetary expenses of travelling to the medical center.

IMPACT OF 3D-PRINTED MODELS FOR SURGICAL PLANNING IN RENAL CELL CARCINOMA WITH VENOUS TUMOR THROMBUS. A RANDOMISED MULTICENTER CLINICAL TRIAL.

To determine whether surgical planning based on 3D models allows for better surgical outcomes than conventional surgical planning in terms of 1) complications, 2) surgical time, and 3) hospital stay. This multicenter clinical trial (NCT03738488) included 66 patients diagnosed with renal cell carcinoma and venous thrombus extension who underwent nephrectomy with thrombectomy. Patients were randomized 1:1 to: 1) surgical planning with conventional images (control group) and 2) surgical planning with 3D-printed models (experimental group). We compared the surgical outcomes of each group in terms of 1) complications, 2) surgical time and 3) hospital stay. The mean surgical time and the mean hospital stay was similar between the groups, although there were more patients with no ICU stay in the 3D group 17 (52%) than in the image group (OR: 3.32 (1.16-9.48)) . There were more patients without any complications in the 3D group (n=18) (OR: 5,40 (1,16-16,53), and among those with complications, there were more severe in the imaging group (n=16) (OR: 20,46 (2,33-178,20)). Surgical planning with 3D printing in renal cell carcinoma and venous thrombus extension compared to conventional planning showed a lower ratio of postoperative complications that helped decrease the ICU stay.

Medical thoracoscopy combined with intrapleural injection of urokinase for treatment of pleural infection-a multicenter, prospective, randomized controlled study: study protocol

BackgroundPleural diseases is a common respiratory disorder, mainly characterized as pleural effusion and patients with pleural effusion caused by pneumonia and empyema constituted 29% of the cohort, which suggests pleural infection as the predominant etiology of pleural effusion in China. Medical thoracoscopy (MT) combined with intrapleural injection of Urokinase holds significant therapeutic value for patients with early to moderate-stage empyema. However, there remains a lack of high-quality evidence regarding the efficacy and safety of combining MT with intrapleural injection of Urokinase administration in patients with pleural infections.MethodsThis study is a prospective, multicenter, randomized controlled clinical trial involving patients with pleural infections. The intervention involves medical thoracoscopy. The control group receives conventional treatment involving intrapleural urokinase injection followed by chest tube placement for drainage. The study outcomes include efficacy and health economic benefits. The estimated minimum sample size for each group is 64 cases, totaling 128 cases. The study groups are delineated as follows: patients in group A receives intrapleural urokinase injection followed by chest tube placement for drainage, while patients in group B undergoes MT to remove multiple septa and necrotic tissue followed by chest tube placement for drainage, and then intrapleural urokinase injection the day after MT. It is recommended that the diameter of the chest tube be 12–14 F, with three daily flushes of 30 ml normal saline to ensure optimal drainage. Subsequently, comprehensive statistical analyses will be conducted to compare treatment effects and complications across all groups, ultimately leading to conclusive findings.DiscussionThe study is the first prospective, multicenter clinical trial on the efficacy and safety of medical thoracoscopy combined with intrapleural urokinase injection for the treatment of pleural infection. This study aims to offer clinical guidance for the management of pleural infection.Registration numberChiCTR2300078352 (Registration Date: 2023/12/06).

The effect of different timings of protein supplementation on variable outcomes in hemodialysis patients: a randomized clinical trial.

Oral nutritional supplements (ONS) are commonly prescribed to provide protein and energy to hemodialysis (HD) patients. There is a debate about the appropriate timing to administer ONS. We aimed to study the effect of different timings of ONS on variable outcomes in HD patients. This research is a prospective, randomized, multicentric clinical trial (RCT) that included 120 patients on regular HD. Patients were allocated to receive ONS (25 gm protein powder/HD session) for 8weeks either predialytic (1h before the start of the session), intradialytic (2h after the start of the session), or interdialytic (on non-dialysis days). Laboratory parameters, blood pressure (BP), dialysis adequacy, and nutritional parameters were assessed during the study. At study end, BP at the end of HD dropped significantly in the intradialytic group compared to the other groups (p < 0.001). Serum albumin improved significantly in the predialytic (p < 0.001) and intradialytic (p = 0.039) groups. The mean subjective global assessment score increased significantly in the interdialytic group (p = 0.040). The Kt/V and urea reduction ratio decreased significantly only in the intradialytic group (p value < 0.001 and 0.001). Serum sodium, potassium, phosphorus, cholesterol, triglycerides, and adverse events did not significantly differ between the different groups. Predialytic ONS supplementation is a favorable option due to improved serum albumin with minimal effects on hemodynamics and dialysis adequacy compared to intradialytic and interdialytic supplementation. ClinicalTrials.gov NCT05953636. First registration date: 1/07/2023.

DOse and administration Time of Indocyanine Green in near-infrared fluorescence cholangiography during laparoscopic cholecystectomy (DOTIG): a randomized clinical trial.

Different techniques have been proposed to reduce the incidence of the intraoperative bile duct injury during laparoscopic cholecystectomy (LC). Among these, Near-Infrared Fluorescence Cholangiography (NIFC) with Indocyanine Green (ICG) represents a relatively recent addition. At present, there is considerable variation in the protocols for the administration of ICG. The aim of this randomized multicenter clinical trial (RCT) is to ascertain whether there are differences between the dosage and administration intervals of ICG, with a view to optimizing a good-quality NIFC during LC. Furthermore, an analysis was conducted to determine the potential impact of different factors on the outcomes of this technique. The trial was approved by the local institutional Ethics Committee. From June 2022 to June 2023, 200 patients were randomized in four arms (G1: 2.5mg ICG > 3h prior to surgery, G2: 2.5mg ICG 15-30min prior to surgery, G3: 0.05mg/kg ICG > 3h prior to surgery and G4: 0.05mg/kg ICG 15-30min prior to surgery). We found differences in the DISTURBED score between the groups (p < 0.001), suggesting that ICG administration 15-30min before surgery was worse than administration > 3h after LC (p = 0.02). Additionally, it was observed that body mass index (BMI), gender, ASA Classification System, previous liver and biliary disease and the type of surgery had influence on NIFC. Finally, the NIFC had an impact in intraoperative and postoperative complications, operative time and hospital length of stay. The administration of ICG > 3h improve liver background fluorescence in the NIFC during LC. There are different factors may affect NIFC results (BMI, ASA grade, previous liver disease, presence of gallbladder inflammation and type of surgery). Finally, high-quality NIFC was associated with fewer surgical complications, shorter surgical time and shorter length of hospital stay.

Safety and Efficacy of Tranexamic Acid in General Surgery

Perioperative bleeding is common in general surgery. The POISE-3 (Perioperative Ischemic Evaluation-3) trial demonstrated efficacy of prophylactic tranexamic acid (TXA) compared with placebo in preventing major bleeding without increasing vascular outcomes in noncardiac surgery. To determine the safety and efficacy of prophylactic TXA, specifically in general surgery. Subgroup analyses were conducted that compared randomized treatment with TXA vs placebo according to whether patients underwent general surgery or nongeneral surgery in the POISE-3 blinded, international, multicenter randomized clinical trial. Participants were 45 years or older, were undergoing noncardiac surgery, had increased cardiovascular risk, and were expected to require at least an overnight hospital admission after surgery. Among 26 581 eligible patients identified, 17 046 were excluded, resulting in 9535 patients randomized to the POISE-3 trial. Participants were enrolled from June 2018 through July 2021. The data were analyzed during December 2023. Prophylactic, 1-g bolus of intravenous TXA or placebo at the start and end of surgery. The primary efficacy outcome was a composite of life-threatening bleeding, major bleeding, or bleeding into a critical organ. The primary safety outcome was a composite of myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism at 30 days. Cox proportional hazards models were conducted, incorporating tests of interaction. Among 9535 POISE-3 participants, 3260 underwent a general surgery procedure. Mean age was 68.6 (SD, 9.6) years, 1740 were male (53.4%), and 1520 were female (46.6%). Among general surgery patients, 8.0% and 10.5% in the TXA and placebo groups, respectively, had the primary efficacy outcome (hazard ratio [HR], 0.74; 95% CI, 0.59-0.93; P = .01) and 11.9% and 12.5% in the TXA and placebo groups, respectively, had the primary safety outcome (HR, 0.95; 95% CI, 0.78-1.16; P = .63). There was no significant interaction by type of surgery (general surgery vs nongeneral surgery) on the primary efficacy (P for interaction = .81) and safety (P for interaction = .37) outcomes. Across subtypes of general surgery, TXA decreased the composite bleeding outcome in hepatopancreaticobiliary surgery (HR, 0.55; 95% CI, 0.34-0.91 [n = 332]) and colorectal surgery (HR, 0.67; 95% CI, 0.45-0.98 [n = 940]). There was no significant interaction across subtypes of general surgery (P for interaction = .68). In this study, TXA significantly reduced the risk of perioperative bleeding without increasing cardiovascular risk in patients undergoing general surgery procedures. ClinicalTrials.gov Identifier: NCT03505723.

Understanding tinnitus symptom dynamics and clinical improvement through intensive longitudinal data

Intensive longitudinal sampling enhances subjective data collection by capturing real-time, dynamic inputs in natural settings, complementing traditional methods. This study evaluates the feasibility of using daily self-reported app data to assess clinical improvement among tinnitus patients undergoing treatment. App data from a multi-center randomized clinical trial were analysed using time-series feature extraction and nested cross-validated ordinal regression with elastic net regulation to predict clinical improvement based on the Clinical Global Impression—Improvement scale (CGI-I). With 50% app compliance (N = 129, 8480 entries), the model demonstrated good fit to the test data (McFadden R2 = 0.82) suggesting its generalizability. Clinical improvement was associated with linear declines in tinnitus-related thoughts, jaw tension, tinnitus loudness, increases in happiness, and variability changes in tinnitus loudness and distress. These findings suggest that daily self-reported data on tinnitus symptoms is sensitive to treatment response and provides insights into specific symptom changes that occur during treatment.

Early Versus Delayed Antihypertensive Treatment After Acute Ischemic Stroke by Hypertension History.

We performed a prespecified subgroup analysis of the CATIS-2 trial (China Antihypertensive Trial in Acute Ischemic Stroke II) to compare the effect of early versus delayed antihypertensive treatment on death and disability in patients with and without medical history of hypertension. CATIS-2 is a multicenter randomized clinical trial conducted in 106 hospitals in China. The trial randomized 4810 patients with acute ischemic stroke within 24 to 48 hours of symptom onset and elevated systolic blood pressure between 140 and <220 mm Hg to receive antihypertensive treatment immediately after randomization or to discontinue antihypertensive medications for 7 days and then receive treatment on day 8. The primary outcome was a combination of death or functional dependency (modified Rankin Scale score ≥3) at 90 days. At the 90-day follow-up, the primary outcome of death or functional dependency was not different between early- and delayed-treatment groups according to the history of hypertension; the odds ratios (95% CIs) associated with the early-treatment group were 1.11 (0.91-1.36) and 1.38 (0.92-2.08) for participants with and without a history of hypertension. However, the ordinal logistic regression showed that early antihypertensive treatment was associated with the odds of a higher modified Rankin Scale score in patients without hypertension (odds ratio, 1.35 [95% CI, 1.01-1.82]), but not in those with hypertension (odds ratio, 0.95 [95% CI, 0.82-1.10]; P=0.04 for interaction). Early antihypertensive treatment did not reduce the odds of dependency or death at 90 days by hypertension history among patients with ischemic stroke but worsened functional outcomes for patients without hypertension in the ordinal analysis. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03479554.

A clinical study of the immunogenicity and protective potency of a live recombinant GamLPV vaccine for intranasal use for the prevention of whooping cough in adult volunteers

Introduction. The increase in incidence rate of pertussis worldwide, short-term insufficient immunity induced by acellular pertussis vaccines (TDaP) and their failure to provide antibacterial protection and to prevent transmission of infection in human population dictate the development of new pertussis vaccines. A new live recombinant pertussis vaccine for intranasal use (GamLPV) has completed preclinical studies in experiments on nonhuman primates and 2 phases of clinical trials involving adult healthy volunteers, in which the safety, immunogenicity and protective activity of the GamLPV were proven. Method and scheme of vaccine administration have been worked out. Aim. Confirmation of the immunogenicity and protective antibacterial potency of GamLPV in a randomized multicenter clinical trial on adult volunteers. Materials and methods. In this multicenter, clinical, randomized, placebo-controlled, double-blind study 260 healthy adults aged 18–65 years were divided into 2 groups: G1 — 210 volunteers (GamLPV) and G2 — 50 volunteers (placebo). 0.25 ml GamLPV delivered to each nostril (5 × 109 CFU) 60 days apart. Levels of Bordetella pertussis-specific IgG, IgA antibodies in blood serum and levels of B. pertussis-specific secretory IgA antibodies in nasopharyngeal aspirates were measured by ELISA method and agglutination test. The dynamics of elimination of attenuated B. pertussis bacteria after the first and second intranasal administration of GamLPV to volunteers was estimated by using qPCR. Results. Significant seroconversion of B. pertussis-specific IgG and IgA antibodies and growth of B. pertussis-specific secretory IgA antibody levels in nasal aspirates of volunteers were demonstrated. The dynamics of changes in the levels of IgG and IgA antibodies indicates a booster effect after second vaccination. Attenuated B. pertussis bacteria persist in the nose/oropharynx of vaccinated volunteers. The period of elimination after second vaccination is more than 2 times shorter than the period after the first one. The number of persistent B. pertussis bacteria after the second vaccination is less than 3% of the values after the first vaccination. Conclusion. High immunogenicity and the formation of antibacterial protection after single and double intranasal vaccination of GamLPV have been proven.

Direct-Acting Oral Anticoagulants in the Management of Cerebral Venous Sinus Thrombosis-Where Do We Stand?

Cerebral venous sinus thrombosis (CVT) is a rare cause of stroke, constituting 0.5-3% of all strokes with an extremely varied spectrum of presentation, predisposing factors, neuroimaging findings, and eventual outcomes. A high index of suspicion is needed because timely diagnosis can significantly alter the natural course of the disease, reduce acute complications, and improve long-term outcomes. Due to its myriad causative factors, protean presentation, and association with several systemic diseases, CVT is encountered not only by neurologists but also by emergency care practitioners, internists, hematologists, obstetricians, and pediatricians. Anticoagulation remains the mainstay of treatment for CVT. Heparin and warfarin previously had been the anticoagulation of choice. Recently there has been an increased interest in utilizing direct-acting oral anticoagulants in the treatment of CVT given comparable safety and efficacy with ease of utilization. However recent clinical guidelines given by multiple societies including the American Stroke guidelines and European guidelines do not include these agents so far in their treatment recommendations. Ongoing multicentric clinical trials are currently reviewing the role of these agents in both short-term as well as long-term. Our review of the literature supports the safety and reinforces the efficacy of DOAC in the treatment of CVT. Additionally, patient satisfaction has been shown to be better with the use of DOAC. In conclusion, DOAC continues to have a valid role in the management of CVT.

The effect of an additional pre-extubational loading dose of caffeine citrate on mechanically ventilated preterm infants (NEOKOFF trial): Study protocol for a multicenter randomized clinical trial.

Minimizing the duration of mechanical ventilation is one of the most important therapeutic goals during the care of preterm infants at neonatal intensive care units (NICUs). The rate of extubation failure among preterm infants is between 16% and 40% worldwide. Numerous studies have been conducted on the assessment of extubation suitability, the optimal choice of respiratory support around extubation, and the effectiveness of medical interventions. Since the Caffeine Therapy for Apnea of Prematurity (CAP) trial, caffeine has become one of the essential drugs at NICUs. However, the optimal dosage and timing for adequate effectiveness still need to be more conclusive. Previous studies suggest that higher doses of caffeine treatment increase the success rate of extubation. Therefore, we aim to determine whether using a single additional loading dose of caffeine citrate one hour prior to extubation impacts the success rate of extubation. The study is an open-label, multicenter randomized clinical trial testing the effectiveness and safety of pre-extubational loading dose of caffeine citrate. Inclusion criteria will be infants born before the 32nd gestational week, before the first extubation attempt after at least 48 hours of mechanical ventilation, and a signed parental informed consent. A total of 226 patients will be randomly allocated to either the experimental or control group. The randomization will be stratified by gestational age and antenatal steroid prophylaxis. Preterm infants in the experimental group will receive an additional intravenous (IV) loading dose (20 mg/kg) of caffeine citrate one hour before the first planned extubation, in addition to the standard dosing regimen (20 mg/kg caffeine citrate IV on the first day of life and 5 to 10 mg/kg IV or orally caffeine citrate each consecutive day). Preterm infants in the control group will receive the standard dosing regimen. The primary outcome will be reintubation within 48 hours. A pre-extubational loading dose of caffeine citrate can reduce extubation failure. Obtaining evidence on this feature has the potential to contribute to finding the optimal dosing regimen. The study protocol was approved by the Hungarian Ethics Committee for Clinical Pharmacology of the Medical Research Council and National Institute of Pharmacy and Nutrition (OGYÉI/6838-11/2023). ClinicalTrials.gov identifier NCT06401083 Registered 06. May 2024.; EudraCT number: 2022-003202-77.

Novel digital leakage notification system can promote better stoma management routines: a multicentre clinical trial.

Most people with a stoma are anxious about stoma-related leakage. To investigate the impact of a novel digital leakage notification system on worry related to stoma leakage, and to evaluate the effect on overall stoma care management. A 12-week interventional, single-arm, multicentre study was conducted in the UK to evaluate the novel digital leakage notification system, including a telemedicine-based support service (=test product), as part of routine stoma care in patients with a recent stoma formation (ClinicalTrials.gov: NCT05135754). Patients completed questionnaires at baseline and at other time points throughout the study period. Study nurses evaluated the test product on individual patient completion of the trial. The intention-to-treat-population consisted of 92 patients. At baseline, 39% of patients worried to a high or very high degree about leakage, which fell to 14% at the final evaluation (P<0.001), at which point patients also reported significantly fewer baseplate changes due to leakage-related worry (P<0.001). The vast majority of nurses reported that the test product helped patients (82%) improve their stoma-care routines (P<0.0001). The use of a digital leakage notification system reduced leakage-related worry and improved stoma self-care.

Novel digital leakage notification system can promote better stoma management routines: a multicentre clinical trial

Background: Most people with a stoma are anxious about stoma-related leakage. Aims: To investigate the impact of a novel digital leakage notification system on worry related to stoma leakage, and to evaluate the effect on overall stoma care management. Method: A 12-week interventional, single-arm, multicentre study was conducted in the UK to evaluate the novel digital leakage notification system, including a telemedicine-based support service (=test product), as part of routine stoma care in patients with a recent stoma formation (ClinicalTrials.gov: NCT05135754). Patients completed questionnaires at baseline and at other time points throughout the study period. Study nurses evaluated the test product on individual patient completion of the trial. Findings: The intention-to-treat-population consisted of 92 patients. At baseline, 39% of patients worried to a high or very high degree about leakage, which fell to 14% at the final evaluation (P&lt;0.001), at which point patients also reported significantly fewer baseplate changes due to leakage-related worry (P&lt;0.001). The vast majority of nurses reported that the test product helped patients (82%) improve their stoma-care routines (P&lt;0.0001). Conclusion: The use of a digital leakage notification system reduced leakage-related worry and improved stoma self-care.

Remediating cognitive inflexibility in obsessive compulsive disorder and anorexia nervosa neither moderates nor mediates treatment effects: an exploratory study.

Obsessive compulsive disorder (OCD) and anorexia nervosa (AN) are conditions associated with poor cognitive flexibility, a factor considered to interfere with treatment, but research into the relationship between cognitive flexibility and treatment outcome is limited. This study explores whether baseline measures of cognitive flexibility predict outcomes in OCD and AN, evaluates whether changes in these measures contribute to treatment outcome, and evaluates the effectiveness of adjunctive cognitive remediation therapy (CRT) in improving cognitive flexibility. This secondary analysis utilized linear mixed model analysis on data from a randomized controlled multicenter clinical trial involving adult participants with OCD (n=71) AND AN (n=61). Participants underwent 10 twice-weekly sessions of either CRT or a non-specific active control intervention (specialized attention therapy; SAT), followed by treatment as usual. Assessments using Yale-Brown Obsessive Compulsive Scale and the Eating Disorder Examination Questionnaire were conducted at baseline, post-CRT/SAT and at 6 and 12 months. Cognitive flexibility was evaluated through the Trail Making Test (TMT), the Color-Word Interference Test (CWIT) and the Detail and Flexibility Questionnaire (DFlex). Levels of cognitive flexibility at baseline did not predict or moderate treatment outcome, nor did change in cognitive flexibility (baseline post-CRT/SAT) mediate treatment outcome, with CRT providing no greater improvement in measures of cognitive flexibility than SAT. This study failed to find any relationship between measures of cognitive flexibility and treatment outcome in OCD and AN, and thus questions hypothetical associations between measures of cognitive flexibility and mechanisms of change in patients with OCD and AN.