Clinical Trials For Treatment Research Articles

Missing outcome data in randomised clinical trials of psychological interventions: a review of published trial reports in major psychiatry journals.

Missing outcome data can pose a serious threat to the validity of randomised clinical trial results. We aimed to study the extent of missing outcome data in randomised clinical trials of psychological interventions. We performed a retrospective study of randomised clinical trial reports of psychological interventions published in World Psychiatry, JAMA Psychiatry, Lancet Psychiatry, American Journal of Psychiatry, British Journal of Psychiatry, or Psychotherapy and Psychosomatics from 2017 to 2022. We assessed the proportion of missing outcome data, whether missing data patterns differed between types of outcomes, participants, intervention lengths, and psychological intervention types, how missing outcome data were handled in the statistical analyses, and whether trialists discussed missing outcome data in the discussion section of the manuscript. We identified 182 randomised clinical trials (233 primary outcomes), of which 206 outcomes (88.4%) were assessed at high risk of bias due to missing data. The overall mean percentage of missing outcome data was 18.3% (95% confidence interval (CI): 16.7-20%) for all outcomes. The percentages of missing data were 18.9% (95% CI: 17.1-20.6%; 180 outcomes) for symptom severity scales and 1.8% (95% CI: 2.3-3.3%; 6 outcomes) for 'hard' binary outcomes. Trials including participants with borderline personality disorder had the highest percentage of missing outcome data (33.1%; 95% CI: 22.3-43.9%) compared with other psychiatric disorders. Fisher's exact test showed that intervention lengths and psychological intervention types were associated with the proportion of missing outcome data (p < 0.001), but there were no clear patterns. Missing outcome data is a considerable problem in randomised clinical trials of psychological interventions, and trialists should consider the corresponding methodological limitations in the design and analysis to reduce the risk of bias due to missing outcome data. Not applicable.

Anti-inflammatory effects of LCB 03-0110 on human corneal epithelial and murine T helper 17 cells.

Dry eye disease (DED) is a complicated disorder that impacts ocular surface and tear-film stability. Inflammation has recently been reported as the core mechanism and main therapeutic target of DED. Although anti-inflammatory drugs have been developed, they still have limited efficacy and various side effects. Recent reports have suggested that kinase inhibitors are beneficial for relieving inflammation. Therefore, this study aimed to investigate the anti-inflammatory effects of LCB 03-0110, a multi-tyrosine kinase inhibitor, on representative cell-based models (HCE- 2 and Th17 cells) of DED. While tacrolimus and tofacitinib, two different anti-inflammatory drugs that have entered clinical trials for DED treatment, did not induce any anti-inflammatory responses in HCE-2 cells, LCB 03-0110 significantly suppressed the phosphorylation of P38 and ERK and reduced the expression levels of IL-6 and IL-8 in HCE-2 cells treated with either LPS or poly(I:C). Moreover, LCB 03-0110 notably decreased the expression level of IL-17A in Th17 cells in a dose-dependent manner, whereas tofacitinib promoted IL-17A production at low concentrations but inhibited its expression at concentrations greater than 1 μM. In addition, LCB 03-0110 was found to be non-toxic to both HCE-2 and Th17 cells. In conclusion, these results suggest that LCB 03-0110 would be a promising drug candidate for the treatment of DED because of its advantages over tacrolimus and tofacitinib.

Abstract B028: Analytical validation of tumor-informed whole genome sequencing analyses for detection of molecular residual disease in solid tumors

Abstract Introduction: Across all patients diagnosed with solid tumors, approximately two-thirds initially present with locoregional disease and are potentially eligible for curative-intent intervention. However, there is a significant subset of patients for which residual tumor cells remain afterwards, potentially leading to disease recurrence. It has been reported that these residual tumor cells, representative of molecular residual disease (MRD), can be detected through analyses of circulating tumor DNA (ctDNA), often earlier than can be achieved through radiographic imaging or clinical presentation. Methods: Labcorp Plasma Detect was utilized to analyze patient-matched tumor, germline (white blood cells), and cell-free or contrived DNA samples through whole genome sequencing at approximately 80x, 40x, and 30x depth, respectively. Raw sequencing data were demultiplexed and trimmed for read quality, then aligned to the hg19 human reference genome. Tumor-specific single nucleotide variants were identified from the tumor and germline datasets and used to determine the presence of cancer within cell-free or contrived DNA samples through a random forest machine learning model. ctDNA status was determined based on the level of signal compared to a reference cohort of noncancerous donor plasma samples (n=80). Results: Analytical specificity was determined through analysis of five noncancerous donor plasma samples with five replicates each, evaluated against 60 somatic mutation profiles obtained from patients with stage III colon cancer, demonstrating a specificity of 99.4% (835/840). Analytical sensitivity was assessed using three contrived cell line models from breast and melanoma tumors, analyzed across three tumor content levels with five replicates at each level and resulted in a limit of detection of 0.005% tumor content using a 100% hit-rate model. Precision, repeatability, and reproducibility were demonstrated within and across runs, operators, and instruments, resulting in a 100% detection rate at 0.05% tumor content with a coefficient of variation of 8.5%. Finally, analytical accuracy compared to an independent tumor-informed ctDNA MRD approach was determined through analysis of 39 clinical cases obtained from patients with bladder, breast, colorectal, and lung cancer, yielding a positive percent agreement of 91% (10/11) and negative percent agreement of 100% (24/24). The prognostic value of ctDNA MRD was demonstrated in stage III colon cancer and clinical validation results for HPV-negative head and neck squamous cell carcinoma will be presented separately. Conclusions: There is significant potential for tumor-informed, non- bespoke MRD approaches for ctDNA detection across a broad range of solid tumor types and curative-intent clinical settings. These data demonstrate the analytical performance of Labcorp Plasma Detect in a CAP/CLIA laboratory for pan-solid tumor research use together with investigational use in early stage colon cancer to support the interventional MEDOCC-CrEATE clinical trial. Citation Format: Kaitlin Victor, Andrew Georgiadis, Ellen Verner, Antoine Simmons, David Riley, James R White, Christopher Greco, Liam Cox, Jesse Fox, Jennifer B Jackson, Eric A Severson, Brian J Caveney, Marcia Eisenberg, Taylor J Jensen, Shakti Ramkissoon, Samuel V Angiuoli, Amy Greer, Kenneth Valkenburg, Mark Sausen. Analytical validation of tumor-informed whole genome sequencing analyses for detection of molecular residual disease in solid tumors [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B028.

The effect of sevelamer on serum calcification propensity in patients with chronic kidney disease: the results of a multicentre, double-blind, placebo-controlled, randomized clinical trial

Abstract Background The serum calcification propensity test (or T50 test) might become a standard tool for the assessment of vascular calcification risk, and T50 might be a valuable biomarker in clinical trials of treatments intended to slow the progression of vascular calcification. Literature data suggest that non-calcium-containing phosphate binders can influence T50 in chronic dialyzed patients. However, it is not clear whether similar interventions are effective in patients at earlier stages of chronic kidney disease (CKD). Methods The “FGF23 Reduction efficacy of a new Phosphate Binder in CKD” (FRENCH) trial was a multi-centre, double-blind, placebo-controlled, randomized trial of sevelamer carbonate in participants with stage 3b/4 CKD. In this subanalysis of the FRENCH data, T50 and other laboratory variables (including fetuin A, and ionized and total magnesium) were measured centrally at baseline and after 12 weeks of treatment. Results A total of 96 patients were screened; 78 (55 men and 23 women) met the inclusion criteria and were randomized to receive placebo (n=39) or sevelamer carbonate (n=39). The median [interquartile range] patient age was 66 [56-72], the median eGFR was 25 [21-30] mL/min/1.73m², and the mean T50 was 335 (82) minutes. In a linear regression model, T50 was independently associated with serum ionized magnesium, fetuin-A and bicarbonate levels; and inversely associated with phosphate concentration. The within-group changes in the mean [95% confidence interval] T50 between week 0 and week 12 were not significant in the sevelamer group or the placebo group (4.6 [-13.6; 22.8] minutes (p=0.61) and 7.8 [-16.4; 32.1] minutes (p=0.51), respectively). Furthermore, we did not observe significant changes in fetuin-A and magnesium levels. Conclusion A 12-week course of the non-calcium-containing phosphate binder sevelamer carbonate was not associated with a significant change in T50 in patients with stage 3b/4 CKD. Phosphate binders might not be an effective strategy for modifying serum calcification propensity in non-dialysis-dependent patients with CKD.

High-throughput proliferation and activation of NK-92MI cell spheroids via a homemade one-step closed bioreactor in pseudostatic cultures for immunocellular therapy.

The NK-92MI cell line has displayed significant promise in clinical trials for cancer treatment. However, challenges persist in obtaining sufficient cell quantities and achieving optimal cytotoxicity. The proliferation of natural killer (NK) cells involves the formation of cell aggregates, but excessively large aggregates can impede nutrient and waste transport, leading to reduced cell survival rates. In this study, a custom bioreactor was designed to mimic pseudostatic culture conditions by integrating brief mechanical rotation during a 6-h static culture period. This method aimed to achieve an optimal aggregate size while improving cell viability. The findings revealed a 144-fold expansion of 3D NK-92MI cell aggregates, reaching an ideal size of 80-150µm, significantly increasing both cell proliferation and survival rates. After 14days of culture, the NK-92MI cells maintained their phenotype during the subsequent phase of cell activation. Moreover, these cells presented elevated levels of IFN-γ expression after IL-18 activation, resulting in enhanced NK cell-mediated cytotoxicity against K562 cells. This innovative strategy, which uses a closed suspension-based culture system, presents a promising approach for improving cell expansion and activation techniques in immunocellular therapy.

Frailty Trajectories Preceding Dementia in the US and UK.

An accessible marker of both biological age and dementia risk is crucial to advancing dementia prevention and treatment strategies. Although frailty is a candidate for that role, the nature of the relationship between frailty and dementia is not well understood. To clarify the temporal relationship between frailty and incident dementia by investigating frailty trajectories in the years preceding dementia onset. Participant data came from 4 prospective cohort studies: the English Longitudinal Study of Ageing, the Health and Retirement Study, the Rush Memory and Aging Project, and the National Alzheimer Coordinating Center. Data were collected between 1997 and 2024 and were analyzed from July 2023 to August 2024. The settings were retirement communities, national-level surveys, and a multiclinic-based cohort. Included individuals were 60 years or older and without cognitive impairment at baseline. Included individuals also had data on age, sex, education level, and ethnicity and a frailty index score calculated at baseline. Frailty was the main exposure, with participants' degrees of frailty quantified using retrospectively calculated frailty index scores. Incident all-cause dementia ascertained through physician-derived diagnoses, self- and informant-report, and estimated classifications based on combinations of cognitive tests. The participant number before exclusions was 87 737. After exclusions, data from 29 849 participants (mean [SD] age, 71.6 [7.7] years; 18 369 female [62%]; 257 963 person-years of follow-up; 3154 cases of incident dementia) were analyzed. Bayesian generalized linear mixed regression models revealed accelerations in frailty trajectories 4 to 9 years before incident dementia. Overall, frailty was positively associated with dementia risk (adjusted hazard ratios [aHRs] ranged from 1.18; 95% CI, 1.13-1.24 to 1.73; 95% CI, 1.57-1.92). This association held among participants whose time between frailty measurement and incident dementia exceeded the identified acceleration period (aHRs ranged from 1.18; 95% CI, 1.12-1.23 to 1.43; 95% CI, 1.14-1.80). These findings suggest that frailty measurements may be used to identify high-risk population groups for preferential enrolment into clinical trials for dementia prevention and treatment. Frailty itself may represent a useful upstream target for behavioral and societal approaches to dementia prevention.

BIOM-17. EVALUATION OF CARBONIC ANHYDRASE TYPE IX (CA IX) EXPRESSION AS TARGET FOR RADIOLIGAND THERAPY IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma represents an unmet need in neuro-oncology. Radioligand therapies are effective and approved in extracranial malignancies such as prostate cancer and neuroendocrine tumors, but data on their use is limited in brain tumors. In addition, rational target selection in gliomas is complicated by tumor heterogeneity. In extracranial tumors, clinical trials of radionuclide treatments targeting carbonic anhydrase IX (CA IX) are ongoing. METHODS Tumor samples of glioblastoma (isocitrate dehydrogenase [IDH]-wildtype) were retrieved from the Neuro-Biobank of the Medical University of Vienna. Formalin-fixed, paraffin-embedded tissue specimen were stained using rabbit anti-CA IX antibody (clone EP161, Cell Marque) on a Ventana Benchmark Ultra platform (Roche Diagnostics). CA IX expression was assessed semiquantitatively. RESULTS Overall, 29 patient samples were included in this study. Median age at surgery was 65 years (range: 55 – 74), and 22/29 (75.9%) were male. Median overall survival (OS) reached 11.6 months (95% confidence interval: 7.3 – 16.3). In total, 24/29 (82.8%) of specimen were positive for CA IX, of whom 20/29 (69.0%) exhibited moderate to high membranous CA IX expression and 4/29 (13.8%) showed weak immunoreactivity. CA IX staining displayed pronounced spatial heterogeneity, as positive areas were primarily seen in pseudo-palisading tumor cells around necrotic foci. Patients with stronger CA IX staining tended to have longer OS (median: 14.2 months) compared to those with absent or weak CA IX expression (median OS: 6.2 months; p = 0.075). Inclusion of further samples of different glioma subtypes is ongoing. CONCLUSIONS CA IX could represent a promising target for radioligand therapy in glioblastoma given the strong CA IX immunoreactivity in most samples. Intratumoral heterogeneity in CA IX expression should be considered in the design of appropriate compounds and the choice of optimal radionuclides to maximize efficacy.

Acute myeloid leukemia in the next-generation sequencing era : Real-world data from an Austrian tertiary cancer care center.

Next-generation sequencing (NGS) has recently entered routine acute myeloid leukemia (AML) diagnostics. It is paramount for AML risk stratification and identification of molecular therapeutic targets. Most NGS feasibility and results data are derived from controlled clinical intervention trials (CCIT). We aimed to validate these data in areal-world setting. This study retrospectively analyzed 447 AML patients treated at an Austrian tertiary cancer care center. A total of 284 out of the 447 cases were treated between 2013-2023 when NGS was locally available for the clinical routine. The NGS was successfully performed from bone marrow biopsies and aspirates, with processing times decreasing from 22days in 2013/2014 to 10days in 2022. Molecular therapeutic target(s) were identified by NGS in 107/284 (38%) cases and enabled risk stratification in 10 cases where conventional karyotyping failed. Concerning molecular landscape, TET2 (27%), FLT3 (25%), DNMT3A (23%), and NPM1 (23%) were most frequently mutated. Comparing older and younger patients (cut-off 70years) showed enrichment in older people for mutations affecting DNA methylation (72% vs.45%; P < 0.001) and the spliceosome (28% vs. 11%; P = 0.006) and more cellular signaling mutations in younger patients (61% vs. 46%; P = 0.022). Treatment outcomes corroborated asignificant survival benefit in the recent NGS era and patients treated with novel/molecularly targeted drugs. Ultimately, biospecimens of these patients are stored within aleukemia biobank, generating avaluable tool for translational science. Our study validates data from CCIT and supports their relevance for treatment decisions in areal-world setting. Moreover, they demonstrate the feasibility and benefits of NGS within aroutine clinical setting.

CNSC-14. GLIOBLASTOMA MULTIFORME TUMOR VOLUME AND PERSISTENCE OF CHIMERIC ANTIGEN RECEPTOR T CELLS FOLLOWING TREATMENT

Abstract Glioblastoma Multiforme (GBM) is one of the most common and aggressive high-grade primary brain tumors that arises from the glial cells of the central nervous system and occurs most often in the frontal and temporal lobes. Despite current treatment options, long-term prognosis of GBM remains low with no significant improvement rates. Chimeric antigen receptor (CAR)-expressing T cells target the B cell marker CD19 and have shown increased efficacy in B cell lymphomas, and lymphoblastic leukemias suggesting benefits in GBM. This study aims to quantify the persistence of CAR-T cells in the context of GBM tumor volume following neurosurgical debulking procedure. A radiology software known as the mint Lesion was utilized to provide Tumor Response Assessment by Criteria (TRAC) reports that consist of volumetric measurements of the tumor lesions (target enhancing lesions, non-target enhancing lesions, and non-target non-enhancing lesions). Fluorescence-activated cell sorting (FACS) analysis takes a sample mixture of cells and sorts them into different populations based on specific biomarkers and characteristics. B7-H3 CAR-T cell persistence was increased in patients with a larger post-surgical tumor volume (3.04% Subject 001 with 2438 mm² volume and 2.38% Subject 003 with 224 mm² tumor volume). However, the number of CAR-T cells per 1 mm² was significantly reduced in patients with a larger post-surgical tumor volume (0.0012 cells/mm² Subject 001 and 0.010 cells/mm² Subject 003). This study shows that although there is an overall increased CAR-T cell persistence for a larger tumor volume, the number of CAR-T cells per 1 mm² is significantly smaller for larger tumor volumes, while illustrating that a larger post-surgical tumor bulk volume is correlated with an increased CAR-T cell persistence within 1-week post-infusion. These findings provide novel information and complement other correlative studies as part of the Phase 1 interventional clinical trial for glioblastoma patients.

Longer-term safety and efficacy of baricitinib for atopic dermatitis in pediatric patients 2 to

Background Baricitinib, an oral selective Janus kinase inhibitor, improved clinical signs and symptoms of moderate-to-severe atopic dermatitis (AD) at week 16 in the phase 3 pediatric study BREEZE-AD-PEDS. Objective To assess longer-term efficacy and safety of baricitinib in pediatric patients aged 2 to <18 years. Methods In BREEZE-AD-PEDS long-term extension, responders and partial responders (validated Investigator Global Assessment-Atopic Dermatitis [vIGA-AD®] 0/1/2) at Week 16 remained on double-blind treatment to which they were randomized (placebo, baricitinib [1-mg equivalent, 2-mg equivalent, or 4-mg equivalent); non-responders (vIGA-AD 3 or 4) at Week 16 transitioned to open-label baricitinib 4-mg equivalent. Safety was summarized for all randomized patients who received ≥1 dose of study treatment. Results In total 467 patients received baricitinib for 750.7 patient-years. Proportion of responders/partial responders (at Week 16) who achieved vIGA-AD 0/1 at Week 52 was greater for baricitinib 4-mg equivalent (56.8%) versus all other treatment groups (42.2%, 47.7%, and 39.7% for 2-mg equivalent, 1-mg equivalent, and placebo, respectively). Most treatment-emergent adverse events were mild/moderate in severity. No deaths, pulmonary emboli, deep vein thromboses or arterial thrombotic events, major adverse cardiovascular events, malignancies, tuberculosis events, or gastrointestinal perforations were reported. Conclusions Baricitinib demonstrated sustained long-term efficacy. No new safety signals were identified. Trial Registration ClinicalTrials.gov Identifier: NCT03952559

Improving treatment outcomes for patients with HER2‑positive breast cancer using neoadjuvant double HER2 blockade

Background. Dual anti-HER2-targeted therapy in breast cancer (BC) significantly increased the rate of pathological complete response (pCR) compared to single blockade when added to chemotherapy. However, limited data exist on the long-term impact on survival of the additional increase in pCR.Aim. To improve recommendations regarding HER2-targeted agents and chemotherapy in the neoadjuvant treatment of BC.Materials and methods. N.N. Petrov National Medical Research Oncology Center, Ministry of Health of Russia took participation in some clinical trials of neoadjuvant treatment of HER2-positive breast cancer, including NeoSphere and NeoALTTO. In multicenter, open-label, phase 2 randomised NeoSphere trial, patients with locally advanced, inflammatory, or early-stage HER2-positive BC were randomly assigned to receive four neoadjuvant cycles of trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2 from every 3 weeks, increasing to 100 mg/m2 from cycle 2 if tolerated) (group A), pertuzumab (420 mg every 3 weeks) and trastuzumab plus docetaxel (group B), pertuzumab and trastuzumab (group C), or pertuzumab and docetaxel (group D). After surgery, patients received three cycles of FEC. Рatients in group C received four cycles of docetaxel prior to FEC, and trastuzumab 6 mg/kg every 3 weeks to complete 1 years treatment. In NeoALTTO trial from 455 patients 154 patients received lapatinib, 149 – trastuzumab, 152 – combination of lapatinib and trastuzumab.Results. Between 2007, and 2009, 417 patients were randomly assigned to group A (107 patients), group B (n = 107), group C (n = 107), or group D (n = 96). At clinical cutoff, 87 patients had disease progression or died. 5-year progressionfree survival rates were 81 % (95 % confidence interval (CI) 71–87) for group A, 86 % (95 % CI 72–91) for group B, 73 % for group C, and 73 % for group D (95 % CI 0.34–1.40). Disease-free survival rates were consistent with progressionfree survival rates and were 81 % (95 % CI 72–88) for group A, 84 % (95 % CI 72–91) for group B, 80 % (95 % CI 70–86) for group C, and 75 % (95 % CI 64–83) for group D. In NeoALTTO trial patients who achieved pCR had longer progressionfree survival (85 % (95 % CI 76–91)) compared with patients who did not achieve pCR (76 % (95 % CI 71–81)).Conclusion. High levels of progression-free survival and disease-free survival at 5–10-years follow-up show large and overlapping CI, but support the primary endpoint (pCR) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. Additionally, they suggest that pCR could be an early indicator of long-term outcome in early-stage HER2-positive BC.

Interim analysis of robot-assisted radical hysterectomy in Japan: a multicenter, prospective interventional single-arm clinical trial

ObjectiveTo investigate the efficacy and safety of robot-assisted radical hysterectomy (RARH) as a minimally invasive procedure in patients with cervical cancer that is curable by surgery.Materials and methodsThis study was a multicenter, open-label, single-arm clinical trial. The short-term outcome of open radical hysterectomy was used as the historical control. The primary endpoint was successful surgery with minimal blood loss (300 mL or less) and negative surgical margins. Secondary endpoints included surgical outcomes, recurrence-free survival (RFS), and overall survival (OS) rates.ResultsOverall, 101 cases were enrolled in this study at 10 participating medical institutions and 100 underwent RARH. Among these cases, 89 met the primary endpoint, exceeding the threshold of 0.75 set by the lower limit. At 2 years postoperatively, 17 cases had recurrences, 4 were classified as International federation of Obstetrics and Gynecology Stage IB1 or lower, while 13 as IB2 or higher. There were three deaths, including one in Stage IB1 and two in Stage IIB in the second postoperative year, all of which had lymph node metastasis. The oncological outcomes for all cases showed RFS and OS rates of 82.7% and 96.9%, respectively, over a median observation period of 37 months. For cases with Stage IB1, RFS and OS were 94.1% and 98.5%, respectively.ConclusionRARH demonstrated a significant reduction in blood loss while ensuring radicality, indicating the safety and efficacy of this procedure compared to conventional RH. Although it is conceivable that the results of this oncological analysis could change, as the data collection has not been fully completed, we plan to further evaluate the oncologic outcomes of RARH in future studies.Trial registrationUMIN-CTR: UMIN000022278, registered on 11th May 2016.

Standardized Patient Communication and Low-Value Spinal Imaging

Acute back pain is a common reason for primary care visits and often results in low-value spinal imaging. To evaluate the effect of a standardized patient-delivered intervention on rates of low-value spinal imaging among primary care patients with acute low back pain. In this randomized clinical trial, physicians or advanced practice clinicians were recruited from March 22 to August 5, 2021, from 10 adult primary care or urgent care clinics in Sacramento, California. The intervention period was from May 1, 2021, to March 30, 2022, with follow-up from October 28, 2021, to June 30, 2023. Analyses were performed from April 1 to June 25, 2024. Clinicians were randomized 1:1 to intervention or control. Intervention clinicians received 3 simulated office visits, each with a standardized patient instructor (SPI) portraying a patient with acute uncomplicated back pain. At each visit, SPIs provided clinician feedback guided by a 3-step model: (1) set the stage for deferred imaging by building trust, (2) convey empathy, and (3) communicate optimism while advocating watchful waiting without imaging. Control clinicians received no intervention. The primary outcome was lumbar spinal imaging completion within 90 days of acute low back pain visits, with study clinicians assessed up to 18 months of follow-up. Secondary outcomes were cervical spine imaging completion after acute neck pain visits, any imaging completion after an adult visit, patient experience ratings of clinicians (scale range, 0-100), and use of targeted communication skills during an audio-recorded standardized patient evaluation visit at median follow-up of 16.8 months (range, 14.1-18.0 months). The analysis included 53 clinicians; mean (SD) age was 46.7 (1.0) years, and 35 (66.0%) reported female gender. A total of 25 were in the intervention group and 28 in the control group. After adjustment for prerandomization rates, patients with acute low back pain who saw intervention and control clinicians during follow-up had similar rates of lumbar imaging (194 of 1234 clinic visits [15.7%] vs 226 of 1306 clinic visits [17.3%]; adjusted ratio of postintervention vs preintervention odds ratios [AORR], 1.00; 95% CI, 0.72-1.40). Adjusted follow-up rates of imaging for acute neck pain (AORR, 1.16; 95% CI, 0.83-1.63) and overall imaging (AORR, 1.07; 95% CI, 0.97-1.19) were not significantly different among patients of intervention and control clinicians. Intervention and control clinicians had similar mean (SD) patient experience ratings during follow-up (88.6 [28.7] vs 88.8 [28.3]; adjusted mean difference-in-differences, -1.0; 95% CI, -3.0 to 0.9). During audio-recorded standardized patient visits, intervention clinicians had significantly better ratings than controls on eliciting the patient's perspective (adjusted standardized difference [ASD], 0.62; 95% CI, 0.05-1.19) and conveying empathy (ASD, 1.16; 95% CI, 0.55-1.77). In this randomized clinical trial of an educational intervention using simulated office visits to encourage a watchful waiting approach for acute low back pain, the intervention had no significant effect on low-value spinal imaging rates or patient experience ratings. ClinicalTrials.gov Identifier: NCT04255199.

Biological effects of combinations of structurally diverse human milk oligosaccharides

Human milk oligosaccharides (HMOs) are a diverse group of structures and an abundant bioactive component of breastmilk that contribute to infant health and development. Preclinical studies indicate roles for HMOs in shaping the infant gut microbiota, inhibiting pathogens, modulating the immune system, and influencing cognitive development. In the past decade, several industrially produced HMOs have become available to fortify infant formula. Clinical intervention trials with manufactured HMOs have begun to corroborate some of the physiological effects reported in preclinical studies, especially modulation of the gut microbiota in the direction of breastfed infants. As more HMOs become commercially available and as HMOs have some shared mechanisms of action, there is a need to better understand the unique and differential effects of individual HMOs and the benefits of combining multiple HMOs. This review focuses on the differential effects of different HMO structural classes and individual structures and presents a scientific rationale for why combining multiple structurally diverse HMOs is expected to exert greater biological effects.

Emicizumab as a Promising Form of Therapy for Type A Hemophilia - A Review of Current Knowledge from Clinical Trials.

Hemophilia is a plasma bleeding disorder characterized by a deficiency of certain blood clotting factors. The most common forms of this disease, i.e., type A and type B, affect approximately 400,000 people worldwide. Without appropriate treatment ensuring the proper coagulation cascade, this disease may lead to serious disability. Minimizing patient discomfort is possible via replacement therapy, consisting of the substitution of a missing coagulation factor via intravenous administration. Frequent medication and the risk related to factor inhibitors are significant disadvantages, necessitating the improvement of current therapies or the development of novel ones. This review examines the humanized bispecific antibody Emicizumab which ensures hemostasis by mimicking the action of the coagulation factor VIII, a deficiency of which causes type A hemophilia. The paper outlines the topic and then summarizes available clinical trials on Emicizumab in type A hemophilia. Several interventional clinical trials have found Emicizumab to be effective in decreasing bleeding episodes and raising patient satisfaction among various hemophilia A populations. Current Emicizumab-related trials are forecast to be completed between 2024 and 2030, and in addition to congenital hemophilia A, the trials cover acquired hemophilia A and patients playing sports. Providing a more comprehensive understanding of Emicizumab may revolutionize the management of hemophilia type A and improve quality of life. Conclusively, Emicizumab is a gentler therapy owing to subcutaneous delivery and fewer injections, which reduces injection-site reactions and makes therapy less burdensome, ultimately decreasing hospital visits and indirect costs.

Impact of the COVID-19 pandemic on participants in pragmatic clinical trials for chronic pain: implications for trial outcomes and beyond.

The COVID-19 pandemic had profound effects on society, including those living with chronic pain. This study sought to examine pandemic impacts on individuals enrolled in pragmatic clinical trials focused on nonpharmacological treatments for chronic pain. We evaluated responses to a questionnaire on COVID-19 impacts that had been administered to participants (n=2024) during study enrollment in 3 pragmatic clinical trials for chronic pain treatment. All trials were part of the National Institutes of Health (NIH)-Department of Veterans Affairs (VA)-Department of Defense (DOD) Pain Management Collaboratory. COVID-19-related impacts on access to health care, mental health, finances, ability to meet basic needs, and social support were assessed. Pandemic impacts were found in all domains assessed, including access to health care, mental and emotional health, ability to meet basic needs, finances, and social support. Impacts varied by demographic and clinical characteristics. The participants most negatively impacted by the pandemic were younger, Black or Latino, female, more educated, and unemployed and had screened positive for depression. No impact differences were found with regard to alcohol use disorder screenings or a prior history of COVID-19. Higher levels of pain were associated with worse pandemic impacts, and negative impacts declined over time. Negative impacts of the pandemic on individuals living with chronic pain cut across aspects of life that are also central to effective pain management, including access to health care, social support, and mental and emotional health, with differential impacts found across key demographic and clinical factors. These findings should yield consideration of pandemic impacts in clinical practice and as moderating effects of treatment outcomes in clinical trials conducted during the pandemic.

Pelvic Binder Radiography Is Safe and Feasible for Quantifying Fracture Instability in LC1 Pelvis Fractures: A Clinical Trial.

To demonstrate fracture displacement, patient tolerance, and in-hospital safety quantifying lateral compression type 1 (LC1) pelvis fracture stability with awake stress radiography using a pelvic binder (PBR). Prospective clinical trial of PBR diagnostic intervention. Two centers, Level I trauma center and academic hospital. Alert adults with LC1 (OTA/AO B1.1/2.1) pelvic fractures from blunt mechanism presenting within 3 weeks of injury between February and December 2023 without hypotension or injury precluding pelvic binder application. The primary outcome was fracture displacement on PBR. Secondary outcomes included feasibility (≥85% patient tolerance) and safety (no major adverse events). Exploratory outcomes included pain during examination, opioid medication consumption within 96 hours, length of hospital stay, discharge destination, and correlation between fracture displacement on PBR and examination under anesthetic. One hundred sixty-nine patients with pelvis fractures were screened, 58 were eligible, and 31 were enrolled. The mean age of enrolled patients was 58.7 ± 23 years, 54.8% were female, 22.6% were White, and 67.7% Hispanic. Fracture displacement was 4.3 ± 4.7 mm on PBR at 5 kg and 8.4 ± 9.0 mm at 10 kg. All patients tolerated PBR. Sixteen patients (52%) reported pain during PBR but completed the test. No patient experienced an adverse event. Patients received 40.4 ± 56.4 mg oral morphine equivalents within 96 hours of PBR. Ten patients (32.2%) received internal fixation. The median hospital stay was 6 days (interquartile range 5.5 days) with no inpatient mortality. Fourteen patients (45.2%) discharged home. PBR is feasible and safe as a point-of-care test for LC1 pelvis fracture instability. Level II Diagnostic.

The influence of intervention fidelity on treatment effect estimates in clinical trials of complex interventions: A meta-epidemiological study

BackgroundRandomized clinical trials (RCT) provide the most reliable estimates of treatment effectiveness for therapeutic interventions. However, flaws in their design and conduct may bias treatment effect estimates, leading to over or underestimation of the true intervention effect. This is especially relevant for complex interventions, such as those in rehabilitation, which are multifaceted and tailored for individual patients or providers, leading to variations in delivery and treatment effects. ObjectiveTo assess whether poor intervention fidelity, the faithfulness of the intervention delivered in an RCT to what was intended in the trial protocol, influences (biases) estimates of treatment effects derived from meta-analysis of rehabilitation RCTs. MethodsIn this meta-epidemiological study of 19 meta-analyses and 204 RCTs published between 2010–2020, we evaluated the difference in intervention effects between RCTs in which intervention fidelity was monitored and those in which it was absent. We also conducted random-effects meta-regression to measure associations between intervention fidelity, risk of bias (ROB), study sample size, and treatment effect estimates. ResultsThere was a linear relationship between fidelity and treatment effect sizes across RCTs, even after adjusting for ROB and study sample size. Higher degrees of fidelity were associated with smaller but more precise treatment effect estimates (d= -0.23 95% CI: -0.38, -0.74). Lower or absent fidelity was associated with larger, less precise estimates. Adjusting for fidelity reduced pooled treatment effect estimates in 4 meta-analyses from moderate to small or from small to no negligible or no effect, highlighting how poor fidelity can bias meta-analyses’ results. ConclusionPoor or absent intervention fidelity in RCTs may lead to overestimation of observed treatment effects, skewing the conclusions from individuals studies and systematic reviews with meta-analyses when pooled. Caution is needed when interpreting the results of complex intervention RCTs when fidelity is not monitored or is monitored but not reported.

The 59th Annual Meeting of the Society for Low Temperature Biology, 20-22 September 2023, Vigo, Spain

Involving patients and their tissues in the research pathway is crucial for future heath innovations. There are many challenges including sustainability, logistical organisation whilst maintaining robust ethical oversight. For over a decade, TAPb has developed to become a research infrastructure to facilitate patient-centric studies across the research pipeline (from bench science, translation to human tissue and the sample component of interventional clinical trials). The TAPb platform groups researchers across academic, commercial and clinical trial sectors, and clinical services. This spreads the costs of the core team, and introduces capacity to provide specialised research services in an incremental way. TAPb is a not-for-profit, full cost recovery model that has been implemented across 7 patient clinical services within the Royal Free London NHS Foundation Trust. It supports an office of 6 fulltime staff, complemented by a number (currently about 7) part-time staff, to reflect the fluctuations in research demand. The researcher journey starts with TAPb linking NHS standard of care and research requirements to aid study design and feasibility. TAPb then provides suitable ethics and project management to develop timescales and delivery methodologies according to evolving research requirements, throughout the delivery phase. Samples and link-anonymised clinical data, and disease interpretation is provided to place samples in the correct research context. This presentation will provide an overview of the important steps which TAPb office have learnt which can make the infrastructure sustainable. Some examples of the significant research impact will be given as an illustration.

Unnecessary exclusion: Eligibility criteria in gynecologic oncology interventional clinical trials impair access to trials

Unnecessary exclusion: Eligibility criteria in gynecologic oncology interventional clinical trials impair access to trials