Clinical Alliance Research Articles

Uptake of health economic evaluations alongside clinical trials in Australia: an observational study.

Australia's clinical trials sector is highly productive with continued sector investment needed to enhance research impact. Generating economic evidence alongside trials has the potential to facilitate the implementation of trial results into practice. Ascertaining the use of health economic evaluations alongside clinical trials can assist in determining whether clinical trials fully realize and operationalize their potential to change policy and practice. The aims of this study were to ascertain the uptake of health economic evaluations alongside Australian-led clinical trials and explore associations between uptake and trial characteristics. This observational study comprised a descriptive analysis of clinical trials registries, a cross-sectional survey of Australian Clinical Trials Alliance (ACTA) networks, and a subgroup analysis of completed acute care trials. Descriptive analyses of trial registrations were conducted, with logistic regressions used to identify predictors of proposing and subsequently publishing a health economic evaluation alongside acute care trials. Few randomized Australian-led clinical trials (11% of 9251) and ACTA network trials (43% of 227) proposed a health economic evaluation. In the subgroup analysis, 22% of the 324 acute care trials and 53% of the 38 ACTA network acute care trials proposed a health economic evaluation. Acute care trials funded by government bodies were significantly more likely to propose and publish a health economic evaluation than those funded by hospitals, universities, and other funders, after adjusting for phase, registration year, primary sponsor type, and comparator. Current uptake of health economic evaluations alongside Australian-led clinical trials is low, with uptake higher among the subset of ACTA network trials. This is despite economic evidence playing an increasingly prominent role in health system management, as well as rising health expenditure, limited budgets, and competing demands. There is significant opportunity to embed health economic evaluations alongside clinical trials, particularly phase 3 trials, to increase research outputs and optimize research translation. Investing in clinical trial networks that support funding for a health economist or a health economic evaluation may be an effective strategy to increase the uptake of health economic evaluations alongside trials.

Predictors of Discordance Between Dry Eye Symptoms and Signs: Insights From the Sjögren's International Collaborative Clinical Alliance.

The diagnosis and management of dry eye disease (DED) could be complicated by the discordance between DED-related symptoms and signs. We performed a cross-sectional study to investigate the factors of and develop predictive models for the discrepancy in DED symptomatology. We used data from 3455 participants, 21 to 89 years old, from the Sjögren's International Collaborative Clinical Alliance study. We performed a multivariable stepwise linear regression model with backward elimination and Bayesian information criteria to select predictors for the discordance in DES symptomatology, which was defined as the difference between the rank score of Ocular Surface Disease Index 6 (OSDI-6) and the rank score of ocular staining score (OSS). Ten predictors, such as "vitality," "immunomodulating drugs," sensory symptoms," and "ethnicity," remained in the final models, achieving an adjusted R2 (aR2) of 0.35 (95% confidence interval [CI], 0.32-0.39). Specifically, medication use explained 19% (95% CI, 0.17-0.22) of the variance in the outcome, followed by medical history (aR2 = 0.18; 95% CI, 0.15-0.21). Health-related quality of life contributed 16% to the variance in the outcome (95% CI, 0.13-0.19), and, last, demographics contributed 11% (95% CI, 0.09-0.13). Our results suggest that individuals of Asian descent and those using immunomodulating medications often present with severe ocular signs that necessitate regular ophthalmological evaluations, even in the absence of proportionate ocular symptoms. Additionally, ocular symptoms, when accompanied by abnormal sensations in other parts of the body, could indicate systemic conditions that require further investigation and medical care.

Comprehensive pan-cancer analysis and experiments revealed R3HDM1 as a novel predictive biomarker for prognosis and immune therapy response.

R3HDM1, an RNA binding protein with one R3H domain, remains uncharacterized in terms of its association with tumor progression, malignant cell regulation, and the tumor immune microenvironment. This paper aims to fill this gap by analyzing the potential of R3HDM1 in diagnosis, prognosis, chemotherapy, and immune function across various cancers. Data was collected from the Firehost database (http://gdac.broadinstitute.org) to obtain the TCGA pan-cancer queue containing tumor and normal samples. Additional data on miRNA, TCPA, mutations, and clinical information were gathered from the UCSC Xena database (https://xenabrowser.net/datapages/). The mutation frequency and locus of R3HDM1 in the TCGA database were examined using the cBioPortal. External validation through GEO data was conducted to assess the differential expression of R3HDM1 in different cancers. Protein expression levels were evaluated using the Clinical Proteomics Tumor Analysis Alliance (CPTAC). The differential expression of R3HDM1 was verified in lung adenocarcinoma cell lines and normal lung glandular epithelial cells via RT-qPCR. Cell migration and proliferation experiments were conducted by knocking down the expression of R3HDM1 in two lung adenocarcinoma cell lines using small interfering RNA. The biological role of R3HDM1 in pan-cancer was explored using the GSEA method. Multiple immune infiltration algorithms from the TIMER2.0 database was employed to investigate the correlation between R3HDM1 expression and the tumor immune microenvironment. Validation of transcriptome immune infiltration was based on 140 single-cell datasets from the TISCH database. The study also characterized a pan-cancer survival profile and analyzed the differential expression of R3HDM1 in different molecular subtypes. The relationship between R3HDM1 and drug resistance was investigated using four chemotherapy data sources: CellMiner, GDSC, CTRP and PRISM. The impact of chemicals on the expression of R3HDM1 was explored through the CTD database. The study revealed differential expression of R3HDM1 in various tumors, indicating its potential as an early diagnostic marker. Changes in somatic copy number (SCNA) and DNA methylation were identified as factors contributing to abnormal expression levels. Additionally, the study found that R3HDM1 expression is associated with clinical features, metabolic pathways, and important pathways related to metastasis and the immune system. High expression of R3HDM1 was linked to poor prognosis across different tumors and altered drug sensitivity. Furthermore, the expression of R3HDM1 showed significant correlations with immune modulatory molecules and biomarkers of lymphocyte subpopulation infiltration. Finally, the study highlighted four chemicals that could influence the expression of R3HDM1. Overall, this study proposes that R3HDM1 expression is a promising biomarker for predicting the prognosis of cancer, especially lung adenocarcinoma, and the efficacy of immunotherapy, demonstrating the rationale for further exploration in the development of anti-tumor therapies.

Discriminative performance of ocular surface staining and lid wiper epitheliopathy in dry eye disease: An investigator-masked, prospective registry-based, diagnostic accuracy study

PurposeTo evaluate the diagnostic performance of corneal and conjunctival staining, and lid wiper epitheliopathy (LWE) in detecting dry eye disease, as defined by the global consensus Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) criteria. MethodsA total of 2066 community residents (1285 females; mean ± SD age, 40 ± 19 years) were recruited in an investigator-masked, prospective registry-based, diagnostic accuracy study. Dry eye symptomology and ocular surface parameters were assessed in a single clinical session. The Sjögren's International Collaborative Clinical Alliance (SICCA) corneal and conjunctival staining scoring and Korb lid wiper epitheliopathy (LWE) grading were evaluated by an independent masked assessor. ResultsOverall, 807 (39 %) participants fulfilled the TFOS DEWS II criteria for dry eye disease, of which 178 (9 %) participants were classified as moderate-to-severe disease. The discriminative abilities of superior and inferior LWE (C-statistics, 0.724 and 0.712, respectively) were greater than corneal and conjunctival staining (C-statistics, 0.573 and 0.627, respectively). The Youden-optimal diagnostic cut-offs for the SICCA corneal and conjunctival staining scores were both ≥1, and the optimal thresholds for the Korb superior and inferior LWE grades were both ≥1. LWE was more commonly detected in both mild-to-moderate and moderate-to-severe dry eye disease, and demonstrated more consistent correlation with other ocular surface parameters across a broader range of disease severity. ConclusionsLWE demonstrates superior diagnostic performance relative to corneal and conjunctival staining. These findings would support the routine incorporation of LWE evaluation as part of the diagnostic workup of dry eye disease.

Ocular surface parameter changes in the untreated fellow eye after unilateral cataract surgery with short-term administration of anti-inflammatory eye drops

This study aimed to investigate the changes in clinical parameters of dry eye disease and meibomian gland dysfunction in both the operated and untreated fellow eyes of patients who underwent unilateral cataract surgery with the short-term administration of anti-inflammatory eye drops in the surgical eye. The medical charts of 57 consecutive patients who underwent unilateral cataract surgery and received 1% prednisolone acetate and non-steroidal anti-inflammatory drug (NSAID, 0.1% bromfenac sodium) eye drops were reviewed. The preoperative ocular surface disease index questionnaire score (38.9 ± 20.5) decreased significantly to 15.2 ± 16.4 at post-surgical 1 week and further to 12.8 ± 11.4 after 1 month. Although meibum quality grade increased and corneal sensitivity decreased at 1 week in operated eyes, corneal erosion scores and Sjogren’s International Collaborative Clinical Alliance ocular staining scores even improved over a month in the untreated fellow eyes. The tear matrix metalloproteinase (MMP)-9 grade decreased in both operated eyes and untreated fellow eyes after 1 month from surgery. In conclusion, the short-term topical anti-inflammatory treatment using steroid and NSAID eye drops in the operated eye after cataract surgery decreased subjective ocular surface discomfort and improved ocular surface staining scores and tear MMP-9 expression in the untreated fellow eyes.

Sjögren's Versus Non-Sjögren's Ocular Features: Similar Symptoms, But Significantly Worse Signs.

To examine the ocular signs and symptoms in participants of the Sjögren's International Collaborative Clinical Alliance cohort, and to compare them across Sjögren's disease (SjD) status. Our study population comprised 3380 Sjögren's International Collaborative Clinical Alliance participants who had no missing data relevant to this study. Participants' SjD status was assessed using the updated 2016 American College of Rheumatism/European League Against Rheumatism SjD classification criteria. Participants completed baseline questionnaires of ocular symptoms and underwent ocular examinations. Differences in the ocular signs and symptoms between SjD and non-SjD groups were assessed. We used multivariable linear and linear mixed-effects models to investigate the impact of SjD on Ocular Surface Disease Index-6 and OSS. Among 1532 participants classified as SjD, their Ocular Surface Disease Index-6 did not clinically differ from those classified as non-SjD (adjusted difference, -0.97; 95% confidence interval, -1.52 to -0.41). However, SjD participants exhibited an elevated ocular staining score (adjusted difference, 3.47; 95% confidence interval, 3.36-3.57; P<0.001) compared with non-SjD participants. In addition, SjD was associated with increased odds of ocular signs, such as reduced tear break-up time, abnormal Schirmer I test, and corneal abnormalities, and was strongly related to more intense corneal and conjunctival staining, as well as additional corneal staining points. SjD is associated with a higher risk of ocular signs and pathology compared with non-SjD, whereas ocular symptoms remain similar. In addition, corneal abnormalities and corneal staining patterns could serve as a potential biomarker in identifying SjD-related dry eye.

Embedding stakeholder preferences in setting priorities for health research: Using a discrete choice experiment to develop a multi-criteria tool for evaluating research proposals

We determined weights for a multi-criteria tool for assessing the relative merits of clinical-trial research proposals, and investigated whether the weights vary across relevant stakeholder groups. A cross-sectional, adaptive discrete choice experiment using 1000minds online software was administered to consumers, researchers and funders affiliated with the Australian Clinical Trials Alliance (ACTA). We identified weights for four criteria—Appropriateness, Significance, Relevance, Feasibility—and their levels, representing their relative importance, so that research proposals can be scored between 0% (nil or very low merit) and 100% (very high merit). From 220 complete survey responses, the most important criterion was Appropriateness (adjusted for differences between stakeholder groups, mean weight 28.9%) and the least important was Feasibility (adjusted mean weight 19.5%). Consumers tended to weight Relevance more highly (2.7% points difference) and Feasibility less highly (3.1% points difference) than researchers. The research or grant writing experience of researchers or consumers was not associated with the weights. A multi-criteria tool for evaluating research proposals that reflects stakeholders’ preferences was created. The tool can be used to assess the relative merits of clinical trial research proposals and rank them, to help identify the best proposals for funding.

An Automated Grading System Based on Topological Features for the Evaluation of Corneal Fluorescein Staining in Dry Eye Disease

Background: Corneal fluorescein staining is a key biomarker in evaluating dry eye disease. However, subjective scales of corneal fluorescein staining are lacking in consistency and increase the difficulties of an accurate diagnosis for clinicians. This study aimed to propose an automatic machine learning-based method for corneal fluorescein staining evaluation by utilizing prior information about the spatial connection and distribution of the staining region. Methods: We proposed an end-to-end automatic machine learning-based classification model that consists of staining region identification, feature signature construction, and machine learning-based classification, which fully scrutinizes the multiscale topological features together with conventional texture and morphological features. The proposed model was evaluated using retrospective data from Beijing Tongren Hospital. Two masked ophthalmologists scored images independently using the Sjögren’s International Collaborative Clinical Alliance Ocular Staining Score scale. Results: A total of 382 images were enrolled in the study. A signature with six topological features, two textural features, and two morphological features was constructed after feature extraction and selection. Support vector machines showed the best classification performance (accuracy: 82.67%, area under the curve: 96.59%) with the designed signature. Meanwhile, topological features contributed more to the classification, compared with other features. According to the distribution and correlation with features and scores, topological features performed better than others. Conclusions: An automatic machine learning-based method was advanced for corneal fluorescein staining evaluation. The topological features in presenting the spatial connectivity and distribution of staining regions are essential for an efficient corneal fluorescein staining evaluation. This result implies the clinical application of topological features in dry-eye diagnosis and therapeutic effect evaluation.

Brazil is gaining its momentum in pharmaceutical development

Brazil is one of the world´s largest economies and pharmaceutical markets, having the Brazilian government as an important purchaser. There are strong local companies that have grown sustainably after the introduction of generics and are investing in both incremental and radical innovation. However, research and development (R&amp;D) expenditures are still modest; this could be explained by a combination of economic and political uncertainty in the past few years and a bureaucratic, complex regulatory framework. New regulations, efforts to reduce ethical and regulatory review timelines, and a Senate bill aimed to accomplish that goal should constitute the definitive regulatory landmark for boosting clinical research. In addition to government investments they have given a breath of relief in the market, as Brazil is trying to, once again, gain momentum as a “must-go” country for clinical development. Non-profit associations such as the Brazilian Society of Pharmaceutical Medicine (Sociedade Brasileira de Medicina Farmacêutica-SBMF), the Brazilian Association of CROs (Associação Brasileira de Organizações Representativas de Pesquisa Clínica-ABRACRO), the Brazilian Clinical Research Alliance (Aliança Pesquisa Clínica Brasil), amongst others, helped to give the impulse to trigger such changes. It is time to invest heavily in developing educational programs to address the growing need for clinical development scientists and physicians.

An Appreciation of a Giant in Orofacial Sciences Research—John Greenspan

Professor John S. Greenspan died on March 31, 2023. He was a renowned and accomplished academic, dentist/scientist, pathologist, and administrator who made sustained and significant international impacts on numerous fields over half a century. John was arguably best known for his work with his wife, Dr. Deborah Greenspan, on the oral aspects of AIDS and the role of viruses in oral epithelial and salivary gland lesions. He had a lifelong interest in Sjögren’s syndrome, culminating in the leadership of the Sjögren’s International Collaborative Clinical Alliance. He was also widely recognized as one of the leading investigators into the understanding of oral mucosal diseases, including recurrent aphthous stomatitis. He and his colleagues’ major contributions to HIV research and care included the discovery of the oral lesion “hairy leukoplakia,” its etiological association with Epstein–Barr virus, and other oral lesions in the natural history of HIV disease. In recent years, John turned his attention to global oral health inequalities, helping to establish the International Association for Dental Research’s Global Oral Health Inequalities Research Network and serving as its first president. He led many organizations with humble authority, knowledge, wit, and wisdom and mentored colleagues from all over the world, especially from lower- and middle-income countries. John leaves a very special legacy based on example and scientific curiosity, and his work has not only made a lasting impact on his colleagues but also translated to abiding benefit for patients.

“You’re stuck in the middle here”: a qualitative study of GPs’ experiences of managing knee pain attributed to a degenerative meniscal tear

BackgroundExercise is the recommended first-line therapy for a degenerative meniscal tear (DMT). Despite this, knee pain attributed to DMTs are a common presentation to specialist orthopaedic clinics. In the primary care setting, the general practitioner (GP) plays a central role in managing patients with knee pain, but to date their perspective has not been explored in relation to DMTs. This study explored GPs’ experiences of managing people with knee pain attributed to a DMT.MethodsA qualitative research design was adopted and practices in the South and Mid-West of Ireland were contacted via recruitment emails circulated through professional and research networks. Interested GPs contacted the researchers via email, and purposive and snowball sampling was used for recruitment. Semi-structured interviews were conducted online or over the telephone. Interviews were digitally recorded and transcribed. Data was analysed using an inductive approach to thematic analysis. Ethical approval was granted by the Irish College of General Practitioners (ICGP_REC_21_0031).ResultsSeventeen semi-structured one-on-one interviews were conducted. Three main themes were identified with related subthemes: (1) GPs’ experiences of relational aspects of care, (2) GP beliefs about what constitutes best care for patients with a DMT, and (3) how GP practice is enacted within the current healthcare setting. GPs described the challenge of maintaining a strong clinical alliance, while managing perceived patient expectations of a ‘quick fix’ and advanced imaging. They reported slowing down clinical decisions and feeling ‘stuck’ with limited options when conservative treatment had failed. GPs believed that exercise should be the core treatment for DMTs and emphasised engaging patients in an active approach to recovery. Some GPs believed arthroscopy had a role in circumstances where patients didn’t improve with physiotherapy. Limited access to public physiotherapy and orthopaedic services hampered GPs’ management plans and negatively impacted patient outcomes.ConclusionsGP beliefs around what constitutes best care for a DMT generally aligned with the evidence base. Nonetheless, there was sometimes tension between these beliefs and the patient’s own treatment expectations. The ability to enact their beliefs was hampered by limited access to conservative management options, sometimes leading to early escalation of care.

Mentor training for junior faculty: a brief evaluation report from the Georgia Clinical and Translational Science Alliance.

To provide a foundation for mentoring, junior faculty participated in a mentor training workshop informed by the Mentoring Clinical and Translational Researchers curriculum. The goal was to develop skills and behaviors that engender more rewarding and inclusive mentoring practices. Attendees responded to baseline and follow-up surveys assessing perceived mentoring skills. Follow-up surveys included closed- and open-ended questions about the value and satisfaction of the training, and intended behavior changes. Junior faculty respondents (n = 39) reported significantly higher overall mentoring skills after the training (t = -2.6, p = 0.012) with a medium effect size (Cohen's D = 0.59). Domains with statistically significant improvement from baseline to follow-up included aligning mentor-mentee expectations and assessing understanding. Thirty-eighty (97%) found the training valuable, and 32 (82%) indicated they would change mentoring-related behaviors because of the training. Intended behavior changes described in open-ended responses aligned with mentoring skills assessed (e.g., aligning expectations). An additional competency domain of evaluating mentoring relationships was also described. A mentor training workshop for junior faculty appeared to contribute to changes in mentoring skills and intended behaviors. Mentor training has the potential to enhance mentorship, which is critical to strengthening a diverse pipeline of clinical and translational science researchers.

410 Successful Implementation of a Cross-Institutional Clinical Research Coordinator Pool to Support Georgia Clinical and Translational Science Alliance (Georgia CTSA) Investigators

OBJECTIVES/GOALS: In 2020 the Georgia CTSA Clinical Research Center site at Emory University developed a highly trained, credentialed research coordinator pool with a goal to expand the pool to include clinical research coordinators from our partner institutions with the ability to work across institutional barriers in support of Georgia CTSA investigators. METHODS/STUDY POPULATION: Fall 2022, an Emory Investigator requested Georgia CTSA Biorepository samples with supporting clinical data for a NIH funded study. This provided a pilot opportunity to utilize clinical research nursing support offered by the UGA Clinical and Translational Research Unit (CTRU). De-identified samples were collected from our Biorepository while Emory’s coordinators and lab collaborated with UGA’s nursing support for data collection. Our obstacle for cross-institutional support was access to Emory Healthcare (EHC) medical records that would be needed by the UGA nurses, but partnerships created with the Georgia CTSA allowed us to overcome this, granting access to the electronic medical records (EMR) needed to complete the study. RESULTS/ANTICIPATED RESULTS: As expected, the process of credentialing and gaining access to the EHC EMR for the UGA team was the most time-consuming in the development of the pool. Discussions began in June 2021 to determine needs to allow the UGA research nurses to support the Emory coordinator pool. Requirements included acquiring an EHC network ID, completion of required Emory research training, letters of support from the Georgia CTSA outlining the collaboration between institutions, and a credentialing application. All steps were completed in May 2022 and the team began to identify studies that could benefit from this collaboration. Given that all credentialing and access needs were in place, the team was able to initiate the study and complete all study requirements, from sample identification to data collection and clean up, in five weeks. DISCUSSION/SIGNIFICANCE: Workforce shortages of experienced clinical research coordinators make it imperative to overcome barriers presented by institutional rules in order to efficiently utilize available resources to conduct high quality research. The CTSAs provide the perfect opportunity for partner institutions to develop processes to allow support across sites.

Prognostic marker C3AR1 is associated with ovarian cancer cell proliferation and immunosuppression in the tumor microenvironment

BackgroundC3AR1 was reported in driving tumor immunity in multiple cancers. However, its roles in ovarian cancer remain unclear. This study aims to determine role of C3AR1 in prognosis and regulating tumor infiltrating immune cells of ovarian cancer (OC).Materials and methodsThe expression, prognosis and clinical data related to C3AR1 were collected from public databases such as The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA) and Clinical Proteomics Tumor Analysis Alliance (CPTAC), and further analyze their relationship with immune infiltration. Immunohistochemistry verified the expression of C3AR1 in ovarian cancer and control tissues. C3AR1 was forced expressed in SKOV3 cells by plasmid transfection, and verified by qRT-PCR and Western blot. Cell proliferation were evaluated by EdU assay.ResultsBioinformatics analysis (TCGA, CPTAC) and immunohistochemical staining of clinical samples confirmed higher C3AR1 expression in ovarian cancer than that in normal tissues. High C3AR1 expression predicted adverse clinical outcomes. KEGG and GO analysis showed that the biological processes of C3AR1 in ovarian cancer are mainly involved in T cell activation, cytokine and chemokine activation. C3AR1 expression was positively correlated with chemokines and their receptors in the tumor microenvironment, such as CCR1(R = 0.83), IL10RA (R = 0.92), and INFG (R = 0.74). In addition, increased C3AR1 expression predicted more infiltration of tumor-associated macrophages, dendritic cell and CD8 + T cell. Some important m6A regulators, such as IGF2BP2, ALKBH5, IGFBP3 and METL14, are significantly positively or negatively correlated with C3AR1. Finally, overexpression of C3AR1 significantly increased proliferation of SKOV3 cells.ConclusionIn summary, our study suggested that C3AR1 is associated with the prognosis and immune cell infiltration of ovarian cancer, and is a promising immunotherapeutic target.

A Relational Agent Intervention for Adolescents Seeking Mental Health Treatment: Protocol for a Randomized Controlled Trial.

Unmet pediatric mental health (MH) needs are growing as rates of pediatric depression and anxiety dramatically increase. Access to care is limited by multiple factors, including a shortage of clinicians trained in developmentally specific, evidence-based services. Novel approaches to MH care delivery, including technology-leveraged and readily accessible options, need to be evaluated in service of expanding evidence-based services to youths and their families. Preliminary evidence supports the use of Woebot, a relational agent that digitally delivers guided cognitive behavioral therapy (CBT) through a mobile app, for adults with MH concerns. However, no studies have evaluated the feasibility and acceptability of such app-delivered relational agents specifically for adolescents with depression and/or anxiety within an outpatient MH clinic, nor compared them to other MH support services. This paper describes the protocol for a randomized controlled trial evaluating the feasibility and acceptability of an investigational device, Woebot for Adolescents (W-GenZD), within an outpatient MH clinic for youths presenting with depression and/or anxiety. The study's secondary aim will compare the clinical outcomes of self-reported depressive symptoms with W-GenZD and a telehealth-delivered CBT-based skills group (CBT-group). Tertiary aims will evaluate additional clinical outcomes and therapeutic alliance between adolescents in W-GenZD and the CBT-group. Participants include youths aged 13-17 years with depression and/or anxiety seeking care from an outpatient MH clinic at a children's hospital. Eligible youths will have no recent safety concerns or complex comorbid clinical diagnoses; have no concurrent individual therapy; and, if on medications, are on stable doses, based on clinical screening and as well as study-specific criteria. Recruitment began in May 2022. As of December 8, 2022, we have randomized 133 participants. Establishing the feasibility and acceptability of W-GenZD within an outpatient MH clinical setting will add to the field's current understanding of the utility and implementation considerations of this MH care service modality. The study will also evaluate the noninferiority of W-GenZD against the CBT-group. Findings may also have implications for patients, families, and providers looking for additional MH support options for adolescents seeking help for their depression and/or anxiety. Such options expand the menu of supports for youths with lower-intensity needs as well as possibly reduce waitlists and optimize clinician deployment toward more severe cases. ClinicalTrials.gov NCT05372913; https://clinicaltrials.gov/ct2/show/NCT05372913. DERR1-10.2196/44940.

Central Corneal Subbasal Nerve Plexus Abnormalities in Sjögren Disease: A Pilot Study.

Small-fiber neuropathy (SFN) is known to be associated with Sjögren disease (SjD), and in vivo corneal confocal microscopy can identify features compatible with SFN. Here, we performed a descriptive study to identify features of SFN of the corneal subbasal nerve plexus using in vivo confocal microscopy. We recruited 10 participants from the Sjögren's International Collaborative Clinical Alliance (SICCA), 1 new participant (in an effort to expand the SICCA cohort), and 22 healthy controls. All participants underwent slit-lamp examination and in vivo confocal microscopy of the central corneal subbasal nerve plexus centered about the central whorl to create a 30-image montage. Each image was analyzed with automated software (ACCmetrics, Manchester, United Kingdom) to produce 7 nerve metrics. We performed t-tests and age-adjusted regressions to make comparisons of nerve metrics between participants with SjD and healthy controls. Most nerve metrics were significantly lower in participants with SjD compared with healthy controls. The mean corneal nerve fiber density was found to be 3.5 mm/mm 2 in participants with SjD compared with 10.6 mm/mm 2 in healthy controls (95% confidence interval, -8.4 to -0.93; P = 0.02). Within the 11 participants with SjD, 22 eyes were analyzed on confocal microscopy, and 16 of those eyes (from 9 individuals) did not have an identifiable central whorl. Within the 22 healthy controls, 22 eyes (right eye alone) were analyzed on confocal microscopy, and 21 of those eyes had an identifiable central whorl. SjD exhibits lower corneal nerve metrics compared with healthy controls. These findings suggest that features compatible with SFN can distinguish SjD from healthy controls and may serve as a potential novel biomarker in identifying SjD.

Identification of Subtypes of Dry Eye Disease, Including a Candidate Corneal Neuropathic Pain Subtype Through the Use of a Latent Class Analysis.

In the absence of a gold-standard diagnostic test for different subtypes of dry eye disease (DED), we aimed to identify latent subtypes of DED within a well-characterized cohort. This is a cross-sectional study of participants enrolled in the Sjögren International Collaborative Clinical Alliance (SICCA). A latent class analysis was applied to different dry eye-related signs/tests and symptoms of ocular pain (particularly those that aligned with corneal neuropathic pain) giving relative specificities and sensitivities of each diagnostic test or symptom in the SICCA population. Four subtypes of DED were identified with putative designations including normal, asymptomatic dry eye, symptomatic dry eye, and corneal neuropathic pain. More specific classification criteria are needed for DED. Latent class analysis applied to the signs and symptoms captured in the SICCA cohort may allow for the development and refinement of classification criteria for specific subtypes of dry eye.

How Are Sicca Signs and Symptoms Associated With Depression Among Men Classified With and Without Sjögren Disease?

Sjögren disease (SjD) cohorts represent rich resources to study associations between dry eye/mouth (sicca) signs/symptoms and depression. Because SjD affects mainly women, little is known about men with sicca signs/symptoms and associations with depression. The Sjögren's International Collaborative Clinical Alliance contained many men allowing for studying associations between sicca signs/symptoms and depression. We hypothesized that sicca symptoms would be positively associated with depression in males. Cross-sectional study. At baseline, participants completed questionnaires and underwent ocular and oral examinations. Depression was assessed using the Patient Health Questionnaire-9. Logistic regression models were used to identify associations between depression and SjD diagnostic criteria and sicca symptoms. Of 309 males, 98 were classified as SjD, whereas 198 were classified as non-SjD. We found that having a labial salivary gland biopsy with focus score ≥1 foci/mm2 was associated with a lower odds of being classified as depressed (odds ratio [OR]: 0.36, 95% CI: 0.18-0.73, P=.01). Having positive anti-Sjögren syndrome antigen A antibody was associated with lower odds of being classified as depressed (OR: 0.44, 95% CI: 0.23-0.88, P=.02). Higher odds of depression were found with ocular burning (OR: 3.16, 95% CI: 1.74-5.73, P < .001), light sensitivity (OR: 2.59, 95% CI: 1.48-4.55, P=.001), and complaints of dry mouth (OR: 4.58, 95% CI: 1.54-13.63, P=.006). Ophthalmologists should be specific when inquiring about ocular discomfort (focusing on burning and light sensitivity) and consider querying about depression and/or providing mental health resources to those who endorse such qualities.

Role of Transarterial Chemoembolization in the Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, transarterial chemoembolization (TACE) is the first-line recommendation for intermediate-stage HCC. In real-world clinical practice, TACE also plays an important role in early- and advanced-stage HCC. This review article by the experts from Chinese Liver Cancer Clinical Study Alliance (CHANCE) summarizes the available clinical evidence pertaining to the current application of TACE in patients with early-, intermediate-, and advanced-stage HCC. In addition, combination of TACE with other treatment modalities, especially immunotherapy, is reviewed.

The utility of the Sydney Melancholia Prototype Index (SMPI) for predicting response to electroconvulsive therapy in depression: A CARE Network study

An enhanced understanding of clinical predictors of positive ECT outcome could assist with the decision to prescribe ECT for select patients. Reliable predictors of ECT response such as psychotic symptoms and age have been identified, however, studies of melancholia and ECT response have been inconsistent. The Sydney Melancholia Prototype Index (SMPI) is a clinical measure designed to differentiate melancholic and non-melancholic depression. This study aimed to investigate whether melancholic depression (as measured by the clinician rated version of the SMPI) predicted a better response to ECT than non-melancholic depression. The study included data collated from four participating sites in the Clinical Alliance for ECT and Related treatments (CARE) network. The primary outcome was response (>50% improvement) on the Montgomery Asberg Depression Rating Scale (MADRS) and the secondary outcome was raw change in MADRS score. Of the 329 depressed patients included in the study, 81% had melancholic features and 76% met criteria for clinical response. SMPI defined melancholia was associated with older age, higher pre-treatment mood scores and presence of psychosis. Melancholia as defined by the SMPI, however, did not significantly predict either clinical response or overall mood improvement with ECT in multivariate analyses. Instead, older age, greater pre-treatment depression severity and the use of bifrontal compared to right unilateral ultrabrief ECT were significant predictors of mood improvement. Path analysis showed that higher pre-treatment mood score and older age were independently associated with mood improvement with ECT.