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Correction: An FGFR-p53 developmental signaling axis drives salivary cancer progression
Get PDFCorrection to "An FGFR-p53 developmental signaling axis drives salivary cancer progression
Design and Interim Recruitment Outcomes of a Multi-Modal, Multi-Level Patient Navigation Intervention for Lung Cancer Screening in the Southeast U.S.
Get PDFBackground/Objectives: Lung cancer is the leading cause of cancer death in the United States (U.S.). Virginia, South Carolina, and North Carolina are among the U.S. states with extraordinarily high rates of lung cancer mortality, particularly among Black residents. The current lung cancer screening guidelines, revised in 2021, support screening for younger, non-Medicare age-eligible individuals who smoke. However, their health insurance, if any, may not cover their screening. This lack of access could create more disparities in lung cancer mortality rates. Methods: To address this concern, the Virginia Commonwealth University Massey Comprehensive Cancer Center, the Medical University of South Carolina Hollings Cancer Center, and the University of North Carolina Chapel Hill Lineberger Comprehensive Cancer Center secured a four-year Stand Up To Cancer® (SU2C) grant titled “Southeastern Consortium for Lung Cancer Screening (SC3) Study” with a novel aim to test the effectiveness of a multimodal, multilevel, barrier-focused patient navigation intervention to promote lung cancer screening among Black patients from federally qualified health centers. Results: A total of 170/675 Black participants have been recruited to date. The majority of participants (n = 134; 78.82%) were aged 55–74 years. Most participants were unmarried (n = 100; 58.82%), more than half had a high school education/GED or less (n = 111; 65.29%), most currently smoked (n = 142; 83.53%), and more males than females participated (n = 107; 62.94% male). Their reported lung cancer screening barriers, addressed by the patient navigators, were cost concerns, insurance coverage issues, and recent medical history precluding screening. Conclusions with Relevance to Cancer Health Equity: This SC3 study includes a unique lung cancer screening cohort that is in direct contrast to the predominantly White cohort in the National Lung Screening Trial. The SU2C study has created a novel, community-engaged approach to lung cancer screening navigation that could become the gold standard in high-risk medically underserved populations
Evaluating Immune-Inflammatory Indices for Risk Stratification in Cardiovascular Disease: An Umbrella Review of Systematic Reviews and Meta-Analyses
Get PDFBackground/Objectives: Although systematic reviews and meta-analyses have examined immune-inflammatory indices in cardiovascular disease (CVD), the evidence remains scattered and inconsistent. This umbrella review aims to synthesize findings and evaluate the overall predictive value of these indices for clinical outcomes. Methods: We systematically searched PubMed, Cochrane Library, Web of Science, Embase, Scopus, and Medline for systematic reviews with meta-analyses assessing neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI) in patients with CVD. Study quality and certainty of evidence were appraised using AMSTAR-2 and GRADE, respectively. Results: A total of 35 meta-analyses covering 106 unique outcomes were included, of which 87 showed significant associations. Elevated NLR and SII were consistently linked to higher risks of CVD mortality, major adverse cardiovascular events, myocardial infarction, heart failure, and stroke. PLR and SIRI were primarily associated with poor recovery from stroke and increased mortality in ST-elevation myocardial infarction. Specifically, the methodological quality of the included reviews was generally moderate to high according to AMSTAR-2, whereas none of the associations reached high certainty based on GRADE, with most rated as low or very low and about one-quarter as moderate certainty. Conclusions: The overall certainty of evidence remains limited according to GRADE, alongside methodological heterogeneity, population variability, and inconsistent thresholds that further restrict the direct applicability of these findings in clinical practice. Nevertheless, available evidence indicates that elevated immune-inflammatory indices are likely associated with worse clinical outcomes in patients with CVD. Future research should prioritize establishing standardized cutoffs, improving methodological consistency, and validating these indices across diverse populations to support their integration into clinical risk-stratification frameworks
Liqi Yangyin formula ameliorates CUMS-induced depression and comorbid constipation via ACE/FFAR2 modulation of the microbiota-gut-brain axis
Get PDFBackground: The gut-brain axis, involving bidirectional signaling between the gastrointestinal tract and the central nervous system. Clinical observations have shown that Liqi Yangyin (LQYY) can effectively relieve symptoms of depression accompanied by constipation. However, whether LQYY exerts its effects through gut-brain crosstalk remains to be elucidated. Methods: A chronic unpredictable mild stress (CUMS) protocol was employed to establish a mouse model. H&E and Nissl staining were used to examine pathological changes in the prefrontal cortex (PFC) and colon. The ultrastructure of the intestinal barrier was observed via transmission electron microscopy, while the expression of the blood-brain barrier tight junction proteins was quantified by Western blotting (WB). ELISA quantified inflammatory factors and serotonin (5-HT) levels. Immunohistochemistry, immunofluorescence, and WB analyzed IBA-1 and Free fatty acid receptor 2 (FFAR2) expression levels. Gut microbiota composition was analyzed via 16S rDNA sequencing, and SCFAs levels were quantified using UHPLC-TSQ Altis Plus. Additionally, in vitro studies using BV-2 cells involved treatments with acetic acid (ACE) and an FFAR2 antagonist, after which the expression of relevant indicators was assessed. Results: Our results demonstrated that LQYY significantly ameliorated CUMS-induced behavioral changes and improved intestinal motility. These effects were associated with the restoration of gut microbiota balance and an increase in ACE levels. LQYY increased FFAR2 expression, leading to reduced neuroinflammation and enhanced colonic 5-HT secretion. Furthermore, LQYY protected intestinal and blood-brain barrier integrity and improved neuronal morphology in the PFC. In vitro studies confirmed that ACE suppresses microglial inflammation through upregulating FFAR2 expression, an effect that was attenuated by the FFAR2 inhibitor GLPG0974. Conclusions: These findings suggest that LQYY modulates the gut-brain axis through ACE/FFAR2, offering a promising therapeutic approach for depression and constipation
Metformin alleviates side effects and supports the resumption of interferon therapy in polycythemia vera and essential thrombocythemia.
Get PDFInterferon-α is emerging as the preferential cytoreductive therapy for polycythemia vera (PV) and essential thrombocythemia (ET) due to improved long-term outcomes over alternatives such as hydroxyurea. Historically, interferon-α therapy has been marked by high rates of adverse events and subsequently poor adherence. Long-acting formulations of interferon-α, i.e., ropeginterferon-α-2b (ropeg), improve tolerability. However, nearly half of ropeg-treated patients experience fatigue, arthralgias, or myalgias and 10-20% discontinue treatment or cannot tolerate maximal ropeg doses, due to adverse events. Herein, we report our retrospective experience of adjunct metformin therapy in 11 PV and ET patients who were intolerant of ropeg. Metformin improved ropeg-related fatigue and/or myalgias in 10 of 11 patients. A complete hematologic response (CHR) was maintained in all 6 patients who had already achieved this prior to starting metformin, and a deepened hematologic response was observed in 3 of 4 patients after the addition of metformin. These encouraging results merit further evaluation in a randomized clinical study. Further, additional investigations are needed to elucidate the mechanism of interferon-α-mediated fatigue and myalgias and the mechanism of putative beneficial interaction between interferon-α and metformin
Optimizing lower intensity triplet therapy in acute myeloid leukemia: a practical guide
Get PDFVenetoclax-based doublets with azacitidine or low dose cytarabine are the standard of care for the treatment of acute myeloid leukemia (AML) in older patients or those unfit for intensive chemotherapy. However, some patients do not attain complete remission, and over time, most patients relapse. Frontline triplet therapy incorporating a targeted therapy (FLT3, IDH or menin inhibitor) is an emerging treatment concept under investigation for this population. Initial triplet regimens have yielded encouraging composite complete remission and measurable residual disease negativity rates, enabling the transition to allogeneic stem cell transplantation for eligible patients. While effective, triplets are associated with myelosuppression and cytopenia-related toxicities, which can affect treatment tolerability and quality of life. In this review, we summarize the available evidence for triplet therapy in AML and offer our recommendations on the practical application of triplets in clinical practice, with particular focus on adjustments to dosing schedules in induction and continuation cycles. We also outline drug-specific adverse effects and interactions based on emerging clinical data to help guide the clinician, given the increasing use of novel combination therapies
Body fluid biomarkers and psychosis risk in The Accelerating Medicines Partnership® Schizophrenia Program: design considerations
Get PDFAdvances in proteomic assay methodologies and genomics have significantly improved our understanding of the blood proteome. Schizophrenia and psychosis risk are linked to polygenic scores for schizophrenia and other mental disorders, as well as to altered blood and saliva levels of biomarkers involved in hormonal signaling, redox balance, and chronic systemic inflammation. The Accelerating Medicines Partnership® Schizophrenia (AMP®SCZ) aims to ascertain biomarkers that both predict clinical outcomes and provide insights into the biological processes driving clinical outcomes in persons meeting CHR criteria. AMP®SCZ will follow almost 2000 CHR and 640 community study participants for two years, assessing biomarkers at baseline and two-month follow-up including the collection of blood and saliva samples. The following provides the rationale and methods for plans to utilize polygenic risk scores for schizophrenia and other disorders, salivary cortisol levels, and a discovery-based proteomic platform for plasma analyses. We also provide details about the standardized methods used to collect and store these biological samples, as well as the study participant metadata and quality control measures related to preanalytical factors that could influence the values of the biomarkers. Finally, we discuss our plans for analyzing the results of blood- and saliva-based biomarkers. Watch Dr. Perkins discuss their work and this article: https://vimeo.com/1062879582?share=copy#t=0
Safety and immunogenicity of novel live attenuated type 1 and type 3 oral poliomyelitis vaccines in healthy adults in the USA: a first-in-human, observer-masked, multicentre, phase 1 randomised controlled trial
Get PDFBackground Reducing the risks of vaccine-derived polioviruses and vaccine-associated paralytic poliomyelitis motivated the development of novel types 1 and 3 oral poliovirus vaccines (nOPV1 and nOPV3, respectively), designed to have similar safety and immunogenicity and improved genetic stability (to reduce risk of reversion to neurovirulence) relative to types 1 or 3 Sabin-strain OPVs. We aimed to assess the safety and immunogenicity of nOPV1 and nOPV3 in healthy adults. Methods We did a first-in-human, observer-masked, multicentre, phase 1 randomised controlled trial in healthy adults at four centres in the USA. Participants were block randomised, stratified by site and according to polio vaccination history (inactivated poliovirus vaccine [IPV] only [hereafter IPV participants] or regimens including OPV [hereafter OPV participants]), and randomly assigned to receive either nOPV or homotypic Sabin-strain monovalent OPV (mOPV). IPV participants received a single dose of nOPV1 or mOPV1 (cohort 1) or nOPV3 or mOPV3 (cohort 3) and OPV participants received two doses 28 days apart of nOPV1 or mOPV1 (cohort 2) or nOPV3 or mOPV3 (cohort 4). The primary outcome was safety among vaccinated participants. Secondary outcomes included homotypic serum neutralising antibody responses measured before and 28 days after each dose in a per-protocol population, and faecal viral shedding mainly in IPV participants assessed up to 56 days following each dose among vaccinated participants. This study was registered with ClinicalTrials.gov (NCT04529538) and is complete. Findings Between May 6, 2021 and Feb 17, 2023, 377 individuals were assessed for eligibility, 226 were randomly assigned, and 205 receive at least one dose of nOPV1 (n=70), mOPV1 (n=45), nOPV3 (n=54), or mOPV3 (n=36). No serious adverse events were observed. Most adverse events were mild, severe events were rare, and solicited events were balanced across groups. Severe solicited events were predominantly fatigue, occurring in 1–4% of participants across all groups except for mOPV1 recipients in whom no such events were reported, and one case of nausea and vomiting in an mOPV1 recipient, and one case of abdominal pain in an nOPV1 recipient. Two (3%) participants in the nOPV1 groups (one reporting severe fatigue, headache, and myalgia, and one reporting abdominal pain) and one (2%) participant in the mOPV1 groups (kidney infection) reported a severe unsolicited adverse event within 28 days. Homotypic seroprotection was nearly 100% at baseline and was 100% 28 days after the first dose. Homotypic seroconversion rates after a single dose were high and similar for nOPV and mOPV (ranging from 86% to 100% for nOPV and from 86% to 93% for mOPV). Similar rates of viral shedding were observed among participants receiving nOPV or mOPV. Peak viral shedding rate detected via PCR among IPV participants was 100% on day 8 after a dose, across groups. Interpretation nOPV1 and nOPV3 were well tolerated and showed similar immunogenicity and shedding profiles to mOPV1 and mOPV3, respectively, supporting progression of these vaccine candidates to phase 2 studies. Funding Bill & Melinda Gates Foundation
Protocol for the process evaluation of a randomised clinical trial of incremental-start versus conventional haemodialysis: the TwoPlus study
Get PDFINTRODUCTION: Process evaluation provides insight into how interventions are delivered across varying contexts and why interventions work in some contexts and not in others. This manuscript outlines the protocol for a process evaluation embedded in a hybrid type 1 effectiveness-implementation randomised clinical trial of incremental-start haemodialysis (HD) versus conventional HD delivered to patients starting chronic dialysis (the TwoPlus Study). The trial will simultaneously assess the effectiveness of incremental-start HD in real-world settings and the implementation strategies needed to successfully integrate this intervention into routine practice. This manuscript describes the rationale and methods used to capture how incremental-start HD is implemented across settings and the factors influencing its implementation success or failure within this trial. METHODS AND ANALYSIS: We will use the Consolidated Framework for Implementation Research (CFIR) and the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) frameworks to inform process evaluation. Mixed methods include surveys conducted with treating providers (physicians) and dialysis personnel (nurses and dialysis administrators); semi-structured interviews with patient participants, caregivers of patient participants, treating providers (physicians and advanced practice practitioners), dialysis personnel (nurses, dieticians and social workers); and focus group meetings with study investigators and stakeholder partners. Data will be collected on the following implementation determinants: (a) organisational readiness to change, intervention acceptability and appropriateness; (b) inner setting characteristics underlying barriers and facilitators to the adoption of HD intervention at the enrollment centres; (c) external factors that mediate implementation; (d) adoption; (e) reach; (f) fidelity, to assess adherence to serial timed urine collection and HD treatment schedule; and (g) sustainability, to assess barriers and facilitators to maintaining intervention. Qualitative and quantitative data will be analysed iteratively and triangulated following a convergent parallel and pragmatic approach. Mixed methods analysis will use qualitative data to lend insight to quantitative findings. Process evaluation is important to understand factors influencing trial outcomes and identify potential contextual barriers and facilitators for the potential implementation of incremental-start HD into usual workflows in varied outpatient dialysis clinics and clinical practices. The process evaluation will help interpret and contextualise the trial clinical outcomes' findings. ETHICS AND DISSEMINATION: The study protocol was approved by the Wake Forest University School of Medicine Institutional Review Board (IRB). Findings from this study will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: NCT05828823
Determining optimal diet/exercise treatment assignment for patients with symptomatic knee osteoarthritis using baseline gait forces.
Get PDFWe examined whether precision medicine models to determine the optimal treatment regimen for participants in an 18-month diet (D), exercise (E), and D + E trial for knee osteoarthritis (KOA) could be further improved with the addition of baseline gait forces (ground reaction, muscle, compressive, and shear forces).We used data from 286 participants in the Intensive Diet and Exercise for Arthritis trial (IDEA). Four machine learning models were used to develop individualized treatment rules for change in outcomes: weight, WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain/function/stiffness, tibiofemoral compressive forces, plasma Interleukin-6 levels, and SF-36 physical component score. We selected the optimal model for each outcome and compared it to the optimal fixed treatment model as well as the optimal model excluding gait forces.We found no statistically significant differences between estimated values of any zero order models (ZOMs) and optimal precision medicine models (PMMs) with gait, nor between optimal PMMs with and without gait. For several outcomes, the optimal PMM without gait performed slightly better than the optimal PMM with gait. The only outcome for which the PMM resulted in a higher estimated value than both the ZOM and the PMM without gait was WOMAC function change.PMMs exhibited no statistically significant differences in estimated values for 18-month change in outcomes when including gait forces. Although potentially underpowered, these results suggest that gait forces, although involved in the KOA phenotype, may not meaningfully influence diet/exercise treatment outcomes for individuals with obesity and symptomatic KOA