Association of Social Determinants of Health with the Likelihood of Treatment with Laser Trabeculoplasty in a United States Database.

PRECIS: Among 1,861 adults with ocular hypertension or mild or moderate primary open-angle glaucoma, those with Medicaid or no insurance had a statistically significantly lower likelihood of receiving laser trabeculoplasty compared with those with other insurance. PURPOSE: To determine whether social determinants of health are associated with undergoing treatment with laser trabeculoplasty (LTP) among individuals with ocular hypertension (OHT) or mild or moderate primary open angle glaucoma (POAG). METHODS: In this cross-sectional study, we included patients with OHT or mild or moderate POAG from the National Institutes of Health All of Us Research Program, a diverse US nationwide dataset. Logistic regression was performed to study the association between LTP treatment status and seven covariates (diagnosis severity, age, gender, race/ethnicity, income, insurance status, and education). RESULTS: 1,861 subjects were included (median age of 72 y). In univariable logistic regression, diagnosis severity, older age, higher income, and insurance (non-Medicaid) were associated with LTP treatment. On multivariable logistic regression models, those with mild POAG (OR, 3.49; 95% CI [2.12-5.87]) and moderate POAG (OR, 7.15 [4.49-11.8]) were still more likely than OHT patients to have received LTP. Moreover, compared with participants with Medicaid or no insurance, participants with other insurance (e.g. employer provided, Medicare) were still more likely to have received LTP (OR, 2.24 [1.08-5.29]). There was no significant difference in the LTP treatment likelihood based on race/ethnicity. CONCLUSIONS: After controlling for confounders, the likelihood of receiving LTP appears to be driven primarily by insurance rather than income or race/ethnicity. Potential reasons for decreased utilization of LTP among Medicaid patients include higher rates of declining the procedure, or LTP may have been offered less frequently due to Medicaid's lower levels of reimbursement and longer reimbursement delays.

Clostridioides difficile superoxide reductase mitigates oxygen sensitivity.

Clostridioides difficile causes a serious diarrheal disease and is a common healthcare-associated bacterial pathogen. Although it has a major impact on human health, the mechanistic details of C. difficile intestinal colonization remain undefined. C. difficile is highly sensitive to oxygen and requires anaerobic conditions for in vitro growth. However, the mammalian gut is not devoid of oxygen, and C. difficile tolerates moderate oxidative stress in vivo. The C. difficile genome encodes several antioxidant proteins, including a predicted superoxide reductase (SOR) that is upregulated upon exposure to antimicrobial peptides. The goal of this study was to establish SOR enzymatic activity and assess its role in protecting C. difficile against oxygen exposure. Insertional inactivation of sor rendered C. difficile more sensitive to superoxide, indicating that SOR contributes to antioxidant defense. Heterologous C. difficile sor expression in Escherichia coli conferred protection against superoxide-dependent growth inhibition, and the corresponding cell lysates showed superoxide scavenging activity. Finally, a C. difficile SOR mutant exhibited global proteome changes under oxygen stress when compared to the parent strain. Collectively, our data establish the enzymatic activity of C. difficile SOR, confirm its role in protection against oxidative stress, and demonstrate SOR's broader impacts on the C. difficile vegetative cell proteome.IMPORTANCEClostridioides difficile is an important pathogen strongly associated with healthcare settings and capable of causing severe diarrheal disease. While considered a strict anaerobe in vitro, C. difficile has been shown to tolerate low levels of oxygen in the mammalian host. Among other well-characterized antioxidant proteins, the C. difficile genome encodes a predicted superoxide reductase (SOR), an understudied component of antioxidant defense in pathogens. The significance of the research reported herein is the characterization of SOR's enzymatic activity, including confirmation of its role in protecting C. difficile against oxidative stress. This furthers our understanding of C. difficile pathogenesis and presents a potential new avenue for targeted therapies.

Current Management of Desmoid Tumors: A Review.

Importance: Desmoid tumor (DT) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Previously, surgery was the standard primary treatment modality; however, within the past decade, a paradigm shift toward less-invasive management has been introduced and an effort to harmonize the strategy among clinicians has been made. To update the 2020 global evidence-based consensus guideline on the management of patients with DT, the Desmoid Tumor Working Group convened a 1-day consensus meeting in Milan, Italy, on June 30, 2023, under the auspices of the European Reference Network on Rare Adult Solid Cancers and Sarcoma Patient Advocacy Global Network, the Desmoid Foundation Italy, and the Desmoid Tumor Research Foundation. The meeting brought together over 90 adult and pediatric sarcoma experts from different disciplines as well as patients and patient advocates from around the world. Observations: The 2023 update of the global evidence-based consensus guideline focused on the positioning of local therapies alongside surgery and radiotherapy in the treatment algorithm as well as the positioning of the newest class of medical agents, such as γ-secretase inhibitors. Literature searches of MEDLINE and Embase databases were performed for English-language randomized clinical trials (RCTs) of systemic therapies to obtain data to support the consensus recommendations. Of the 18 full-text articles retrieved, only 4 articles met the inclusion criteria. The 2023 consensus guideline is informed by a number of new aspects, including data for local ablative therapies such as cryotherapy; other indications for surgery; and the γ-secretase inhibitor nirogacestat, the first representative of the newest class of medical agents and first approved drug for DT. Management of DT is complex and should be carried out exclusively in designated DT referral centers equipped with a multidisciplinary tumor board. Selection of the appropriate strategy should consider DT-related symptoms, associated risks, tumor location, disease morbidities, available treatment options, and preferences of individual patients. Conclusions and Relevance: The therapeutic armamentarium of DT therapy is continually expanding. It is imperative to carefully select the management strategy for each patient with DT to optimize tumor control and enhance quality of life.

Antenatal creatine supplementation reduces persistent fetal lung inflammation and oxidative stress in an ovine model of chorioamnionitis.

Chorioamnionitis is a common antecedent of preterm birth and induces inflammation and oxidative stress in the fetal lungs. Reducing inflammation and oxidative stress in the fetal lungs may improve respiratory outcomes in preterm infants. Creatine is an organic acid with known anti-inflammatory and antioxidant properties. The objective of the study was to evaluate the efficacy of direct fetal creatine supplementation to reduce inflammation and oxidative stress in fetal lungs arising from an in utero proinflammatory stimulus. Fetal lambs (n = 51) were instrumented at 90 days gestation to receive a continuous infusion of creatine monohydrate (6 mg·kg-1·h-1) or saline for 17 days. Maternal chorioamnionitis was induced with intra-amniotic lipopolysaccharide (LPS; 1 mg, O55:H6) or saline 7 days before delivery at 110 days gestation. Tissue creatine content was assessed with capillary electrophoresis, and inflammatory markers were analyzed with Luminex Magpix and immunohistochemistry. Oxidative stress was measured as the level of protein thiol oxidation. The effects of LPS and creatine were analyzed using a two-way ANOVA. Fetal creatine supplementation increased lung creatine content by 149% (PCr < 0.0001) and had no adverse effects on lung morphology. LPS-exposed groups showed increased levels of interleukin-8 in the bronchoalveolar lavage (PLPS < 0.0001) and increased levels of CD45+ leukocytes (PLPS < 0.0001) and MPO+ (PLPS < 0.0001) cells in the lung parenchyma. Creatine supplementation significantly reduced the levels of CD45+ (PCr = 0.045) and MPO+ cells (PCr = 0.012) in the lungs and reduced thiol oxidation in plasma (PCr < 0.01) and lung tissue (PCr = 0.02). In conclusion, fetal creatine supplementation reduced markers of inflammation and oxidative stress in the fetal lungs arising from chorioamnionitis.NEW & NOTEWORTHY We evaluated the effect of antenatal creatine supplementation to reduce pulmonary inflammation and oxidative stress in the fetal lamb lungs arising from lipopolysaccharide (LPS)-induced chorioamnionitis. Fetal creatine supplementation increased lung creatine content and had no adverse effects on systemic fetal physiology and overall lung architecture. Importantly, fetuses that received creatine had significantly lower levels of inflammation and oxidative stress in the lungs, suggesting an anti-inflammatory and antioxidant benefit of creatine.

Adaptive designs in dermatology clinical trials: Current status and future perspectives.

Current drug development strategies present many challenges that can impede drug approval by regulatory agencies. Alternative study models, such as adaptive trial designs, have recently sparked interest, as they provide a flexible and more efficient approach in conducting clinical trials. Adaptive trial designs offer several potential benefits over traditional randomized controlled trials, which include decrease in costs, reduced clinical development time and limiting exposure of patients to potentially ineffective treatments allowing completion of studies with fewer patients. This article explores the current use of adaptive trial designs in non-oncologic skin diseases and highlights the most common types of adaptive designs used in the field. We also review the operational challenges and statistical considerations associated with such designs and propose clinical development strategies to successfully implement adaptive designs. The article also proposes instances where adaptive trial designs are particularly beneficial, and other situations where they may not be very useful.

Incidence and Outcomes of Hypertensive Phase After Glaucoma Drainage Device Surgery.

PURPOSE: To describe the incidence, risk factors, clinical characteristics, and long-term outcomes of a hypertensive phase (HP) after glaucoma drainage device (GDD) implantation. DESIGN: Retrospective cohort study. PARTICIPANTS: Eyes that underwent implantation of their first GDD from January 2010 to October 2020 at a tertiary care center. METHODS: Hypertensive phase was defined as intraocular pressure (IOP) >21 mmHg occurring at 2 consecutive visits in the first 90 days after the date of surgery for Ahmed Glaucoma Valve (AGV) or in the first 90 days after tube opening for Baerveldt Glaucoma Implant (BGI). Generalized estimating equations and Fisher exact tests were used to evaluate risk factors for HP and risk factors for failure of GDD surgery after occurrence of a HP. MAIN OUTCOME MEASURES: Incidence and risk factors for HP. Overall surgical success rates, defined as the absence of failure criteria: IOP >21 mmHg, ≤5 mmHg, or <20% reduction below baseline IOP after 3 months for 2 consecutive visits, with or without adjunctive ocular hypotensive therapy; additional glaucoma surgery; or loss of light perception. RESULTS: Among 419 eyes of 360 patients that underwent GDD implantation, 42 (10.0%) eyes developed HP. Onset of HP was 20.8 ± 10.5 days after AGV and 11.7 ± 20.3 days from the date of tube opening after BGI. Mean IOP during HP was 26.5 ± 3.2 mmHg with peak IOP of 30.0 ± 5.9 mmHg. Median follow-up duration was 21.5 months after onset of HP. Younger age and neovascular glaucoma were significant risk factors for HP occurrence in a multivariable model. Resolution of HP occurred in 32 eyes (76.2%) after a mean duration of 48.0 ± 53.0 days. Additional surgery with a second GDD or cyclophotocoagulation was performed for 12 eyes (28.6%). The overall success rate among eyes with a HP was 52.6% at 2 years, which was significantly lower than that observed among control eyes that did not experience HP (76.3%), P < 0.01. CONCLUSIONS: The incidence of HP was 10.0%. Younger age and neovascular glaucoma were significant risk factors for HP in the multivariable model. The risk of surgical failure after HP is significantly higher compared to eyes that did not experience HP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Intraluminal Suture Placement for Management of Hypotony After Glaucoma Drainage Device Surgery.

PRCIS: Intraluminal 3-0 Supramid stent placement can be an effective long-term solution for hypotony after glaucoma drainage device surgery. This procedure may obviate the need for conjunctival dissection. In some cases, additional procedures are required. PURPOSE: To describe the utility of implantation of a multifilament polyamide suture (Supramid) in the tube lumen to reverse hypotony after glaucoma drainage device (GDD) surgery. PATIENTS: Patients who underwent tube revision with intraluminal placement of a 3-0 Supramid stent, with or without external ligature, to manage hypotony following GDD surgery between January 2010-October 2020. METHODS: Resolution of hypotony was defined as IOP >5 mmHg and the absence of hypotony-related structural abnormalities. Overall success was the absence of failure criteria (IOP ≤5 mmHg, >21 mmHg, or <20% reduction below baseline IOP after 3 months for 2 consecutive study visits; additional glaucoma surgery; or loss of light perception), with or without adjunctive ocular hypotensive therapy. RESULTS: Nine eyes of 9 patients underwent placement of a 3-0 Supramid stent with resolution of hypotony in all eyes with mean follow-up duration of 33.3 ±24.0 months. Overall success was achieved in 7 of 9 eyes. Four eyes required intervention after stent placement: 1 eye required selective laser trabeculoplasty followed by replacement of the original stent with a shorter 3-0 Supramid suture and external ligature; 1 eye underwent revision for tube exposure; and 2 eyes underwent laser suture lysis to release an external suture ligature. CONCLUSIONS: In cases of hypotony after GDD, particularly when it is desirable to reduce the extent of additional conjunctival dissection, intraluminal placement of a 3-0 Supramid stent via an intracameral approach can be an effective long-term solution. Post-operative adjustments were required in many cases.

Targeted genomic sequencing of avian influenza viruses in wetland sediment from wild bird habitats.

Diverse influenza A viruses (IAVs) circulate in wild birds, including highly pathogenic strains that infect poultry and humans. Consequently, surveillance of IAVs in wild birds is a cornerstone of agricultural biosecurity and pandemic preparedness. Surveillance is traditionally done by testing wild birds directly, but obtaining these specimens is labor intensive, detection rates can be low, and sampling is often biased toward certain avian species. As a result, local incursions of dangerous IAVs are rarely detected before outbreaks begin. Testing environmental specimens from wild bird habitats has been proposed as an alternative surveillance strategy. These specimens are thought to contain diverse IAVs deposited by a broad range of avian hosts, including species that are not typically sampled by surveillance programs. To enable this surveillance strategy, we developed a targeted genomic sequencing method for characterizing IAVs in these challenging environmental specimens. It combines custom hybridization probes, unique molecular index-based library construction, and purpose-built bioinformatic tools, allowing IAV genomic material to be enriched and analyzed with single-fragment resolution. We demonstrated our method on 90 sediment specimens from wetlands around Vancouver, Canada. We recovered 2,312 IAV genome fragments originating from all eight IAV genome segments. Eleven hemagglutinin subtypes and nine neuraminidase subtypes were detected, including H5, the current global surveillance priority. Our results demonstrate that targeted genomic sequencing of environmental specimens from wild bird habitats could become a valuable complement to avian influenza surveillance programs.IMPORTANCEIn this study, we developed genome sequencing tools for characterizing avian influenza viruses in sediment from wild bird habitats. These tools enable an environment-based approach to avian influenza surveillance. This could improve early detection of dangerous strains in local wild birds, allowing poultry producers to better protect their flocks and prevent human exposures to potential pandemic threats. Furthermore, we purposefully developed these methods to contend with viral genomic material that is diluted, fragmented, incomplete, and derived from multiple strains and hosts. These challenges are common to many environmental specimens, making these methods broadly applicable for genomic pathogen surveillance in diverse contexts.

Prediction and Detection of Glaucomatous Visual Field Progression Using Deep Learning on Macular Optical Coherence Tomography.

PRCIS: A deep learning model trained on macular OCT imaging studies detected clinically significant functional glaucoma progression and was also able to predict future progression. OBJECTIVE: To use macular optical coherence tomography (OCT) imaging to predict the future and detect concurrent visual field progression, respectively, using deep learning. DESIGN: A retrospective cohort study. SUBJECTS: A pretraining data set was comprised of 7,702,201 B-scan images from 151,389 macular OCT studies. The progression detection task included 3902 macular OCT imaging studies from 1534 eyes of 828 patients with glaucoma, and the progression prediction task included 1346 macular OCT studies from 1205 eyes of 784. METHODS: A novel deep learning method was developed to detect glaucoma progression and predict future progression using macular OCT, based on self-supervised pretraining of a vision transformer (ViT) model on a large, unlabeled data set of OCT images. Glaucoma progression was defined as a mean deviation (MD) rate of change of ≤ -0.5 dB/year over 5 consecutive Humphrey visual field tests, and rapid progression was defined as MD change ≤ -1 dB/year. MAIN OUTCOME MEASURES: Diagnostic performance of the ViT model for prediction of future visual field progression and detection of concurrent visual field progression using area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. RESULTS: The model distinguished stable eyes from progressing eyes, achieving an AUC of 0.90 (95% CI, 0.88-0.91). Rapid progression was detected with an AUC of 0.92 (95% CI, 0.91-0.93). The model also demonstrated high predictive ability for forecasting future glaucoma progression, with an AUC of 0.85 (95% CI 0.83-0.87). Rapid progression was predicted with an AUC of 0.84 (95% CI 0.81-0.86). CONCLUSIONS: A deep learning model detected clinically significant functional glaucoma progression using macular OCT imaging studies and was also able to predict future progression. Early identification of patients undergoing glaucoma progression or at high risk for future progression may aid in clinical decision-making.

Effect of Early Aqueous Suppression After Valved Tube Shunt Surgery for Uveitic Glaucoma.

PURPOSE: To compare outcomes of early aqueous suppression (EAS) and standard therapy (ST) after Ahmed Glaucoma Valve (AGV) implantation for uveitic glaucoma. DESIGN: Retrospective comparative cohort study. PARTICIPANTS: All patients with uveitic glaucoma underwent AGV implantation from January 2010 to October 2020 at Northwestern Medicine. METHODS: Excluding the first postoperative day 1 (POD1), only eyes with IOP 10-15 mmHg at their first visit with IOP ≥ 10 mmHg were included in the main analysis. Early aqueous suppression (EAS) was defined as initiation of ocular hypotensive therapy when IOP was first 10-15 mmHg. Standard therapy was initiation of therapy at any later time. Failure was defined as IOP > 21 mmHg, < 5 mmHg, or < 20% reduction in IOP from baseline after 3 months, for 2 consecutive study visits. Hypotony was defined as IOP ≤ 5 mmHg for ≥ 2 visits. Hypertensive phase was defined as IOP > 21 mmHg for 2 consecutive visits in the first 3 months. MAIN OUTCOME MEASURES: Proportion achieving overall success; incidence of hypotony and hypertensive phase. RESULTS: Twenty-eight eyes of 26 patients were in the EAS group and 20 eyes of 19 patients were in the ST group, with a mean follow-up of 17.7 and 28.2 months, respectively. Baseline IOP was similar in the EAS (31.2 ± 10.1 mmHg) and ST (34.6 ± 12.2 mmHg) groups; P = 0.18. Final IOP was lower in the EAS group (12.9 ± 4.6 mmHg) than the ST group (16.4 ± 5.7 mmHg; P = 0.02) on 2.6 ± 0.9 medications in the EAS group and 1.8 ± 1.5 in the ST group (P = 0.07). Overall success was achieved in 87% of EAS eyes and 74% of ST eyes (P = 0.43). There were no statistically significant differences in the occurrence of additional glaucoma surgery (4% for EAS, 20% for ST; P = 0.11), hypotony (7% for EAS, 0% for ST; P = 0.50), or hypertensive phase (4% for EAS, 21% for ST; P = 0.09). CONCLUSIONS: EAS was associated with a lower final IOP after AGV in uveitic glaucoma eyes; however, more medications were in use at the final visit. No statistically significant differences in overall success or the incidence of adverse events were observed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Implications of headwater contact zones for the riverine barrier hypothesis: a case study of the Blue-capped Manakin (Lepidothrix coronata).

Rivers frequently delimit the geographic ranges of species in the Amazon Basin. These rivers also define the boundaries between genetic clusters within many species, yet river boundaries have been documented to break down in headwater regions where rivers are narrower. To explore the evolutionary implications of headwater contact zones in Amazonia, we examined genetic variation in the Blue-capped Manakin (Lepidothrix coronata), a species previously shown to contain several genetically and phenotypically distinct populations across the western Amazon Basin. We collected restriction site-associated DNA sequence data (RADcap) for 706 individuals and found that spatial patterns of genetic structure indicate several rivers, particularly the Amazon and Ucayali, are dispersal barriers for L. coronata. We also found evidence that genetic connectivity is elevated across several headwater regions, highlighting the importance of headwater gene flow for models of Amazonian diversification. The headwater region of the Ucayali River provided a notable exception to findings of headwater gene flow by harboring non-admixed populations of L. coronata on opposite sides of a < 1-km-wide river channel with a known dynamic history, suggesting that additional prezygotic barriers may be limiting gene flow in this region.

International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors.

BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. METHODS: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication. RESULTS: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. CONCLUSION: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses.

Dimethyl fumarate modulates the dystrophic disease program following short-term treatment.

New medicines are urgently required to treat the fatal neuromuscular disease Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory small molecule nuclear erythroid 2-related factor 2 activator with current clinical utility in the treatment of multiple sclerosis and psoriasis that could be effective for DMD and rapidly translatable. Here, we tested 2 weeks of daily 100 mg/kg DMF versus 5 mg/kg standard-care prednisone (PRED) treatment in juvenile mdx mice with early symptomatic DMD. Both drugs modulated seed genes driving the DMD disease program and improved force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects, protected contracting muscles from fatigue, improved histopathology, and augmented clinically compatible muscle function tests. DMF may be a more selective modulator of the DMD disease program than PRED, warranting follow-up longitudinal studies to evaluate disease-modifying impact.

Principles of Child Health Care Financing.

The American Academy of Pediatrics believes that the United States can and should ensure that all children, adolescents, and young adults from birth through the age of 26 years who reside within its borders have affordable access to high-quality comprehensive health care. Comprehensive, high-quality care addresses issues, challenges, and opportunities unique to children and young adults and addresses the effects of historic and present inequities. All families should have equitable access to professionals and facilities with expertise in the care of children within a reasonable distance of their residence. Payment methodologies should be structured to guarantee the economic viability of the pediatric medical home and of pediatric specialty and subspecialty practices. The recent increase in child uninsurance over the last several years is a threat to the well-being of children and families in the short- and long-term. Deficiencies in plans currently covering insured children pose similar threats. The AAP believes that the United States must not sacrifice recent hard-won gains for our children and that child health care financing should be based on the following guiding principles: (1) coverage with quality, affordable health insurance should be universal; (2) comprehensive pediatric services should be covered; (3) cost sharing should be affordable and should not negatively affect care; (4) payment should be adequate to strengthen family- and patient-centered medical homes; (5) child health financing policy should promote equity and address longstanding health and health care disparities; and (6) the unique characteristics and needs of children should be reflected.

Population Health in Pediatric Primary Care as a Means to Achieving Child Health Equity.

We propose population health as a model of care to advance efforts to achieve child health equity. We use the structure-process-outcome framework to highlight key structures of pediatric population health necessary to catalyze what has been slow progress to date. Using specific ongoing examples, we then show how different models of integrated health care delivery systems align population health structures to enable processes aimed to achieve child health equity. We conclude by highlighting the critical role of committed leadership to drive progress.

Developing a clinical research infrastructure embedded in an academic medicine center that equitably supports future clinician scientists.

Clinical research in academic medical centers can be difficult to conduct and meet enrollment goals. Students under-represented in medicine (URiM) are also under-represented in academic leadership positions and as physician-scientists but are critical to help solve health disparities. Barriers in pursuing medicine as a career may be high for URiM students, therefore it is important to create pre-medicine opportunities accessible to all students interested in healthcare careers. We describe an undergraduate clinical research platform, the Academic Associate (AcA) program, embedded in the medical system that supports clinical research for academic physician scientists and provides students equitable access to experiences and mentoring opportunities. Students have the opportunity of completing a Pediatric Clinical Research Minor (PCRM) degree. This program satisfies many pre-medicine opportunities for undergraduate students, including those URiM, and allows access to physician mentors and unique educational experiences for graduate school or employment. Since 2009, 820 students participated in the AcA program (17.5% URiM) and 235 students (18% URiM) completed the PCRM. Of the 820 students, 126 (10% URiM) students matriculated to medical school, 128 (11%URiM) to graduate school, and 85 (16.5% URiM) gained employment in biomedical research fields. Students in our program supported 57 publications and were top-enrollers for several multicentered studies. The AcA program is cost-effective and achieves a high level of success enrolling patients into clinical research. Additionally, the AcA program provides equitable access for students URiM to physician mentorship, pre-medical experiences, and an avenue to early immersion in academic medicine.

The Prognostic Role of the Immune Microenvironment in Sinonasal Intestinal-Type Adenocarcinoma: A Computer-Assisted Image Analysis of CD3+ and CD8+ Tumor-Infiltrating Lymphocytes.

The prognostic value of conventional histopathological parameters in the sinonasal intestinal-type adenocarcinoma (ITAC) has been debated and novel variables should be investigated. Increasing evidence demonstrated that the evolution of cancer is strongly dependent upon the complex interactions within tumor microenvironment. The aim of this retrospective study was to assess the features of immune microenvironment in terms of CD3+ and CD8+ cells in a series of ITAC and explore their prognostic role, as well as their relations with clinicopathological variables. A computer-assisted image analysis of CD3+ and CD8+ tumor-infiltrating lymphocytes (TIL) density was conducted on surgical specimens of 51 patients with ITAC that underwent a curative treatment including surgery. ITAC displays variable TIL density, which is associated with OS. In a univariate model, the density of CD3+ TIL was significantly related to OS (p = 0.012), whereas the association with CD8+ TIL density resulted in being non-significant (p = 0.056). Patients with intermediate CD3+ TIL density were associated with the best outcome, whereas 5-year OS was the lowest for intermediate CD8+ TIL density. CD3+ TIL density maintained a significant association with OS in the multivariable analysis. TIL density was not significantly related to demographic and clinicopathological variables. CD3+ TIL density was independently associated with OS in a non-linear fashion and patients with intermediate CD3+ TIL density had the best outcome. Though based on a preliminary analysis on a relatively small series of patients, this finding makes TIL density a potential independent prognostic factor of ITAC.

Effectiveness and Safety of Trabectedin and Radiotherapy for Patients With Myxoid Liposarcoma: A Nonrandomized Clinical Trial.

Importance: Preclinical data about the synergistic activity of radiotherapy (RT) and trabectedin have been reported. The combination of trabectedin and RT in treating myxoid liposarcomas appears worth exploring. Objective: To explore the effectiveness and safety of trabectedin combined with RT. Design, Setting, and Participants: This international, open-label, phase 2 nonrandomized clinical trial including 46 patients with myxoid liposarcoma was conducted in 4 centers in Spain, 1 in Italy, and 2 in France from July 1, 2016, to September 30, 2019. Eligible patients had to have a histologic, centrally reviewed diagnosis of localized resectable myxoid liposarcoma arising from an extremity or the trunk wall. Interventions: Trabectedin was administered at the recommended dose stemming from the phase 1 trial (1.5 mg/m2), with intravenous infusion during 24 hours every 21 days for a total of 3 cycles. Radiotherapy was started after completion of the first trabectedin infusion (cycle 1, day 2). Patients received 25 fractions of radiation for a total of 45 Gy. Surgery was planned 3 to 4 weeks after the administration of the last preoperative cycle and not until 4 weeks after the end of preoperative RT. Pathologic specimens were mapped in tumor sections to estimate the histologic changes and the percentage of viable tumor after neoadjuvant treatment. Main Outcomes and Measures: The primary objective of the phase 2 part of the study was overall response. Secondary objectives were effectiveness measured by relapse-free survival and activity measured by functional imaging and pathologic response. Results: A total of 46 patients were enrolled. Four patients were not evaluable. The median age was 43 years (range, 18-77 years), and 31 patients were male (67%). Overall, 9 of 41 patients (22%) achieved a partial response with neoadjuvant treatment with trabectedin and RT, with 5 of 39 patients (13%) achieving a complete pathologic response and 20 of 39 patients (51%) having 10% or less of a viable remaining tumor. Partial responses according to Choi criteria were observed in 24 of 29 evaluable patients (83%), and no patient had disease progression. Treatment was well tolerated. Conclusions and Relevance: Although the primary end point of this phase 2 nonrandomized clinical trial was not met (Response Evaluation Criteria in Solid Tumors response in ≥70% of patients), results suggest this combination was well tolerated and effective in terms of pathologic response. Thus, trabectedin plus RT might be a treatment option regarding tolerability; further evidence should be generated in this setting.