Faculty Bibliography

OBJECTIVE:Under-representation of key population groups limits the generalizability, applicability, and equity of evidence generated by gynecologic oncology trials. Building on the Gynecologic Cancer InterGroup Barcelona consensus, this initiative aimed to translate the principles of diversity into a structured, practice-oriented Code of Conduct spanning all phases of clinical research. METHODS:As the third step in an iterative Gynecologic Cancer InterGroup consensus process, a Code of Conduct was developed and formally adopted at the Gynecologic Cancer InterGroup Berlin Meeting. All 33 Gynecologic Cancer InterGroup member groups appointed delegates. Preparatory work included a comprehensive literature review, structured meetings of an interdisciplinary scientific committee, and the NOGGO-GCIG-IDEA survey on equity, diversity, and inclusion. A plenary session included individuals with lived experience, clinicians, and researchers from multiple continents. Statements were drafted in focused working groups and refined to consensus. RESULTS:The resulting Code of Conduct provides actionable guidance across 12 domains: transparent inclusion criteria; standardized data collection, analysis, and reporting; ethnicity considerations; patient-centered communication and consent; reducing the burden of participation; ethics and scientific integrity; data and biospecimen sharing; governance, accountability, and oversight; global collaboration and capacity building; post-trial responsibilities; authorship, acknowledgment, and dissemination; and implementation and continuous improvement. Harmonized collection of diversity variables is recommended to enable international comparison. CONCLUSION/CONCLUSIONS:Diversity is a prerequisite for scientific validity and clinical relevance rather than an optional consideration. By embedding diversity into every phase of research, the Gynecologic Cancer InterGroup Code of Conduct provides a framework to generate robust, generalizable, and inclusive evidence for the global gynecologic oncology community. The Code is endorsed by the European Society of Gynaecological Oncology and the International Federation of Gynecology and Obstetrics and will be reviewed biennially.

Withania somnifera (L.) Dunal, commonly known as ashwagandha, has been widely used in Ayurvedic medicine for its adaptogenic properties and therapeutic potential and has been investigated for its benefits related to sleep and stress management by Western medicine. However, concerns regarding its teratogenic and abortifacient effects have emerged following reports from the World Health Organization (WHO) and regulatory bodies. This systematic and ethnobotanical review critically evaluates these claims by assessing ashwagandha's toxicokinetics, toxicodynamics, and available safety data. A comprehensive literature review following PRISMA guidelines was conducted to identify studies on its reproductive toxicity, molecular interactions, and traditional usage. Historical ethnobotanical reports suggest potential abortifacient effects, but citation distortion and lack of primary source validation raise concerns regarding the validity of such claims. Toxicological studies in animal models demonstrate high tolerability, with no significant reproductive toxicity observed at doses relevant to human consumption. Human clinical studies also show no adverse effects on thyroid function, hormonal balance, or reproductive health. Altogether, evidence supporting significant teratogenic or abortifacient activity remains inconclusive. This review highlights the need for standardized, high-quality research addressing fertility and developmental outcomes in controlled conditions. Given the widespread use of ashwagandha as a dietary supplement ingredient and traditional medicine, a balanced and evidence-based approach is required to assess its safety, ensuring that regulatory actions are informed by robust scientific data rather than historical speculation.

OBJECTIVES/OBJECTIVE:The COVID-19 pandemic highlighted an urgent need to more efficiently identify patients at highest risk for developing respiratory failure. We investigated whether plasma levels of lung injury biomarkers are associated with progression to respiratory failure among adults hospitalized with COVID-19 pneumonia without respiratory failure at admission. DESIGN/METHODS:This was a nested case-control study of COVID-19 patients enrolled in the Accelerating COVID-19 Therapeutic Interventions and Vaccines-3 (ACTIV-3)/Therapeutics for Inpatients with COVID-19 (TICO) platform trial who were on less than 20 L/min supplemental oxygen at enrollment. We compared baseline measurements of lung injury biomarkers between participants who progressed to respiratory failure or died by study day 10 (cases) and matched controls who did not progress to respiratory failure or death. Cases and controls were matched 1:1 on age, baseline oxygen requirement, immunomodulator use, and study arm. SETTING/METHODS:Hospitals enrolling in the ACTIV-3/TICO trials. PATIENTS/METHODS:Four hundred five cases and 405 matched controls. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Baseline levels of plasma interleukin (IL)-6, IL-8, IL-18, tumor necrosis factor receptor, angiopoietin-2, soluble receptor for advanced glycation end-products (sRAGE), C-reactive protein (CRP), and surfactant protein D (SPD) were compared between cases and controls using matched logistic regression. Forward variable selection was used to identify biomarkers that were independently associated with progression to respiratory failure or death in a multivariate model. All lung injury biomarkers with the exception of SPD were significantly associated with progression to respiratory failure or death, with sRAGE demonstrating the highest odds ratio (OR) for each doubling of biomarker level (OR, 1.85; 95% CI, 1.61-2.12). In multivariate regression analysis, sRAGE, IL-6, and CRP were independently associated with progression, with sRAGE as the biomarker with the strongest association. CONCLUSIONS:Baseline levels of plasma lung injury biomarkers are significantly associated with progression to respiratory failure or death among hospitalized COVID-19 patients without respiratory failure at admission. These findings support the potential utility of measuring lung injury biomarkers in patients hospitalized without respiratory failure and should be tested in more heterogeneous patient groups including non-COVID-19 cohorts.

In response to declining public trust in healthcare institutions, the Institute for Healthcare Improvement (IHI) and the American Board of Internal Medicine Foundation (ABIMF) began a collaborative to identify changes that healthcare organizations could make to regain the trust of their care teams and communities. Using IHI and ABIMF's theory of change as a guide, six healthcare organizations tested this framework on-site and shared lessons learned, identifying the critical role of not just acknowledging past breaches but also demonstrating accountability as crucial steps to strengthening trust. The experiences of three healthcare organizations are summarized here.

Pancreatic ductal adenocarcinoma (PDAC) is a complex disease characterized by high levels of cellular heterogeneity and pronounced microenvironmental remodelling. Dynamic changes during its initiation and progression contribute to resistance to conventional therapies. Building upon key molecular catalogues established by bulk and single-cell profiling studies that have advanced our understanding of PDAC biology, recent advances in spatial biology have provided much-needed insights by elucidating regionally compartmentalized transcriptomic and proteomic programmes within the PDAC microenvironment. In parallel, emerging computational frameworks in digital pathology and artificial intelligence have advanced the field into a high-dimensional, quantitative discipline, particularly for classifying molecular and clinical features from histopathology images. Despite these advancements, integration of these two modalities remains a major challenge. Here, we summarize the convergence of molecular features identified through spatially resolved profiling in PDAC and its precursor lesions, as well as current developments in AI-powered pathology in cancer research. We further propose a multi-modal integration framework that maps molecular states onto morphological and architectural phenotypes, offering a roadmap for spatially informed patient stratification beyond descriptive tissue characterization. We posit that the path forward relies on disciplined cross-scale integration of spatial, histological, and clinical data to ensure meaningful translation into clinical practice.

BACKGROUND:Chronic low back pain (cLBP) is often managed conservatively, but it is vital to rule out certain causes before pursuing targeted treatment. A thorough evaluation, including medication reconciliation, ensures appropriate care and may prevent costly or invasive treatments for many ubiquitous conditions, including patients taking statin medications. CASE REPORT/METHODS:We present a series of 3 cases in which patients on statin medication presented to a pain management clinic with symptoms initially resembling mechanical and/or radicular chronic LBP (cLBP). In all 3 cases, medication reconciliation revealed high-dose statin medication, and supervised dose reduction or discontinuation was temporally linked with the alleviation of symptoms. CONCLUSION/CONCLUSIONS:This is the first known case series reporting suspected statin-associated muscle symptoms that mimic lumbar radiculopathy. These cases underscore the importance of comprehensive clinical evaluation, including medication reconciliation. Clinicians should consider medication-related side effects in the differential diagnosis of new or atypical musculoskeletal pain.

Synucleinopathies are a group of neurodegenerative disorders characterized by the accumulation of aggregated α-synuclein (α-syn), including Parkinson's disease, Dementia with Lewy Bodies, and Multiple System Atrophy. These diseases are marked by locomotor and non-motor impairments, as well as mitochondrial dysfunction and the loss of dopaminergic (DA) neurons. We have developed several anti-α-syn single-domain antibodies (sdAbs) and demonstrated the diagnostic imaging potential of two of them and the acute therapeutic benefit of one in clearing α-syn in a mouse model. However, whether these sdAbs can suppress α-syn-mediated neuronal loss and locomotor impairment in vivo remains unclear. We evaluated the therapeutic potential of five anti-α-syn sdAbs to clear pathological α-syn in mouse neuronal culture and then demonstrated their in vivo efficacy in a Drosophila model of synucleinopathy. The sdAbs differed in their efficacy to lower levels of phospho-serine 129 α-syn, prevent loss of DA neurons, alleviate mitochondrial dysfunction, improve motor function, and prolong survival in synucleinopathy flies. The most effective sdAb, 2H1, has not been reported before. It binds strongly to the aggregation prone region of α-syn and robustly improves all these disease parameters. Additionally, that sdAb is associated with α-syn in the fly neurons, as shown through proximity dependent turboID biotinylation assays. The sdAb-turboID also biotinylated α-syn-associated proteins involved in synapse/vesicle trafficking pathways, pinpointing the location of their intracellular interaction. Our findings provide an insight into the therapeutic mechanism of action of these sdAbs and strongly support their clinical development.

INTRODUCTION/BACKGROUND:Survival outcomes among patients with World Health Organization grade III gliomas and IDH-mutant (IDHmt) gliomas treated with immunotherapy (IT) remain understudied, with most research focusing on grade IV (G4) glioblastomas or IDH wild-type (IDHwt) tumors. METHODS:A systematic literature search was conducted in PubMed/MEDLINE, SCOPUS, Embase, Google Scholar, and Science Direct databases following PRISMA guidelines. A random-effects meta-analysis was conducted to assess overall survival and 5-year mortality. Outcomes were compared across IT treatments and between historically designated grade III versus grade IV/GBM cohorts and explicitly reported IDHmt versus IDHwt glioma cohorts within each included study. RESULTS:A total of 21 studies involving 207 patients with grade III gliomas and 11 studies involving 115 patients with IDHmt gliomas were included. IT agents studied included dendritic cell and peptide vaccines (32 grade III, 45 IDHmt), immune checkpoint inhibitors (1 grade III, 39 IDHmt), oncolytic viruses (10 grade III, 20 IDHmt), modified lymphocyte therapies (1 grade III, 11 IDHmt), cytokine immunotherapy (47 IDHmt) and radioimmunotherapy (110 grade III). Most treated grade III (65.6%) and IDHmt (72.7%) gliomas were recurrent tumors. Across all immunotherapy agents, recurrent and newly diagnosed grade III glioma did not exhibit significant differences in overall survival (21.90 versus 29.71 months, p = 0.237), 5-year mortality (77.10% versus 60.89%, p = 0.481), or overall mortality at last follow-up (78.91% versus 70.37%, p = 0.553). Newly diagnosed IDHmt glioma had significantly greater overall survival than recurrent IDHmt glioma (43.13 versus 19.57 months, p = 0.005) and significantly lower 5-year mortality (10.26% versus 59.78%, p < 0.001). Between immunotherapy modalities, grade III glioma did not exhibit differences in overall survival compared to GBM in equivalent treated cohorts (p = 0.123). However, dendritic cell and peptide vaccines had a higher overall survival compared to all other immunotherapy agents in IDHmt glioma (p = 0.002), including when compared to IDHwt glioma in equivalent treatment arms (p = 0.044). CONCLUSION/CONCLUSIONS:Our study summarizes reported survival outcomes among patients with historically designated grade III and IDHmt gliomas treated with immunotherapy. Observed differences by histological grade, IDH status, and recurrence status are consistent with the established prognostic importance of these tumor features, and should not be interpreted as evidence that immunotherapy caused improved survival. Survival outcomes appeared more favorable in newly diagnosed IDHmt glioma and in IDHmt cohorts treated with dendritic cell or peptide vaccines; however, these findings are descriptive and hypothesis-generating given the predominance of single-arm studies, limited sample size, and potential confounding by baseline prognosis. Future prospective controlled trials are needed to determine whether specific immunotherapy approaches provide benefit in these glioma subgroups.