HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease: HLA DQA1*05 and Pediatric Crohn's Disease.

Objectives: HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data.

Methods: We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs.

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

Background: Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab).

Travel Time to Treating Center is Associated With Diagnostic Delay in Pediatric Inflammatory Bowel Disease.

Background & Aims: Delayed diagnosis of inflammatory bowel disease (IBD) leads to prolonged symptoms and worse long-term outcomes. We sought to evaluate whether race, ethnicity, disease type, and social factors are associated with delayed diagnosis of pediatric IBD.

Methods: We performed a cross-sectional study of newly diagnosed pediatric patients with IBD at 22 United States sites from 2019 to 2022.

Novel Combination Treatment for Melanoma: FLASH Radiotherapy and Immunotherapy Delivered by a Radiopaque and Radiation Responsive Hydrogel.

Immunotherapies have become the standard treatment for melanoma. To further improve patient responses, combinations of immunotherapies and radiotherapy (RT) are being studied, since radiotherapies can potentially provide additional immune stimulation, in addition to direct antitumor effects. FLASH-RT is a novel, ultrahigh dose rate, radiation delivery approach, with the potential of at least equivalent tumor control efficacy and reduced damage to healthy tissue.

A Prospective Phase I/II Clinical Trial of High-Dose Proton Therapy for Chordomas and Chondrosarcomas.

Purpose: The purpose of this study was to evaluate the feasibility and safety of dose-escalated proton beam therapy for treating chordomas and chondrosarcomas of the skull base and spine. Methods: A prospective cohort of 54 patients (42 with chordomas and 12 with chondrosarcomas) was enrolled between 2010 and 2018. The primary endpoints were feasibility and <20% rate of acute grade ≥3 toxicity, and secondary endpoints included cancer-specific outcomes and toxicities.

An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma.

Cancer immunity is subjected to spatiotemporal regulation by leukocyte interaction with neoplastic and stromal cells, contributing to immune evasion and immunotherapy resistance. Here, we identify a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). We reveal a spatially restricted, Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which tumor ECs produce osteopontin to promote immunosuppressive macrophage (Mφ) phenotypes.

Spatial analysis of tissue immunity and vascularity by light sheet fluorescence microscopy.

The pathogenesis of cancer and cardiovascular diseases is subjected to spatiotemporal regulation by the tissue microenvironment. Multiplex visualization of the microenvironmental components, including immune cells, vasculature and tissue hypoxia, provides critical information underlying the disease progression and therapy resistance, which is often limited by imaging depth and resolution in large-volume tissues. To this end, light sheet fluorescence microscopy, following tissue clarification and immunostaining, may generate three-dimensional high-resolution images at a whole-organ level.

Reconstituting Spore Cortex Peptidoglycan Biosynthesis Reveals a Deacetylase That Catalyzes Transamidation.

Some bacteria survive in nutrient-poor environments and resist killing by antimicrobials by forming spores. The cortex layer of the peptidoglycan cell wall that surrounds mature spores contains a unique modification, muramic-δ-lactam, that is essential for spore germination and outgrowth. Two proteins, the amidase CwlD and the deacetylase PdaA, are required for muramic-δ-lactam synthesis in cells, but their combined ability to generate muramic-δ-lactam has not been directly demonstrated.

Abundance, distribution, and composition of microplastics in the filter media of nine aged stormwater bioretention systems.

Bioretention systems are designed for quality treatment of stormwater. Particulate contaminants are commonly treated efficiently and accumulate mainly in the surface layer of the bioretention filter material. However, concerns exist that microplastic particles may not show equal accumulation behavior as other sediment particles.

Monitoring the effects of urban and forested land uses on runoff quality: Implications for improved stormwater management.

Urban stormwater is a substantial source of non-point source pollution. Despite considerable monitoring efforts, little is known about stormwater quality in certain geographic regions. These spatial gaps induce uncertainty when extrapolating data and reduce model calibration capabilities, thereby limiting pollutant load reduction strategies.

Gamma Knife radiosurgery for trigeminal neuralgia provides greater pain relief at higher dose rates.

In Gamma Knife (GK) radiosurgery, dose rate decreases during the life cycle of its radiation source, extending treatment times. Prolonged treatments influence the amount of sublethal radiation injury that is repaired during exposure, and is associated with decreased biologically-equivalent dose (BED). We assessed the impact of treatment times on clinical outcomes following GK of the trigeminal nerve - a rare clinical model to isolate the effects of treatment times.

Digital Point Solutions for Extending Contact Tracing Capacity.

Background: Initial COVID-19 surges in the United States created a need for technology to supplement human resources to increase efficiency and efficacy.

Methods: Resolve to Save Lives worked with jurisdictions to co-design four technology solutions-Epi Viaduct data pipeline, Epi Contacts contact elicitation webform, Epi Locator contact information search plugin, and Epi Viewpoint case management system (CMS)-to expand the capacity of case investigation and contact tracing (CI/CT) teams. We assessed impact on reducing CI/CT time intervals for COVID-19 using product data and user feedback.

mutant small cell glioblastoma in a patient with Gorlin syndrome: A case report.

Gorlin syndrome or nevoid basal cell carcinoma syndrome is a rare genetic disease characterized by predisposition to congenital defects, basal cell carcinomas and medulloblastoma. The syndrome results from a heritable mutation in (), causing constitutive activation of the Hedgehog pathway. The present study described a patient with Gorlin syndrome who presented early in life with characteristic basal cell carcinomas and later developed a small cell glioblastoma (GBM), World Health Organization grade IV, associated with a Patched 1 () mutation.

Occurrence, concentration, and distribution of 38 organic micropollutants in the filter material of 12 stormwater bioretention facilities.

The increased use of bioretention facilities as a low impact development measure for treating stormwater runoff underscores the need to further understand their long-term function. Eventually, bioretention filter media must be (partly) replaced and disposed of at the end of its functional lifespan. While there are several studies of metal accumulation and distributions in bioretention media, less is known about organic pollutant pathways and accumulation in these filters.

Personalized Research on Diet in Ulcerative Colitis and Crohn's Disease: A Series of N-of-1 Diet Trials.

Introduction: Evidence about specific carbohydrate diet (SCD) for inflammatory bowel disease (IBD) is limited. We conducted 54 single-subject, double-crossover N-of-1 trials comparing SCD with a modified SCD (MSCD) and comparing each with the participant's baseline, usual diet (UD).

Methods: Across 19 sites, we recruited patients aged 7-18 years with IBD and active inflammation.

Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma.

Malignant solid tumors are characterized by aberrant vascularity that fuels the formation of an immune-hostile microenvironment and induces resistance to immunotherapy. Vascular abnormalities may be driven by pro-angiogenic pathway activation and genetic reprogramming in tumor endothelial cells (ECs). Here, our kinome-wide screening of mesenchymal-like transcriptional activation in human glioblastoma (GBM)-derived ECs identifies p21-activated kinase 4 (PAK4) as a selective regulator of genetic reprogramming and aberrant vascularization.

Standards of Practice for Occupational Therapy.

This document defines minimum standards for the practice of occupational therapy. According to the Occupational Therapy Practice Framework: Domain and Process (4th ed.; OTPF-4), occupational therapy is defined as the therapeutic use of everyday life occupations with persons, groups, or populations (i.

On pandemics and pivots: a COVID-19 reflection on envisioning the future of medical education.

The required adjustments precipitated by the coronavirus disease 2019 crisis have been challenging, but also represent a critical opportunity for the evolution and potential disruptive and constructive change of medical education. Given that the format of medical education is not fixed, but malleable and in fact must be adaptable to societal needs through ongoing reflexivity, we find ourselves in a potentially transformative learning phase for the field. An Association for Medical Education in Europe ASPIRE Academy group of 18 medical educators from seven countries was formed to consider this opportunity, and identified critical questions for collective reflection on current medical education practices and assumptions, with the attendant challenge to envision the future of medical education.

Integration of Deep Learning Radiomics and Counts of Circulating Tumor Cells Improves Prediction of Outcomes of Early Stage NSCLC Patients Treated With Stereotactic Body Radiation Therapy.

Purpose: We develop a deep learning (DL) radiomics model and integrate it with circulating tumor cell (CTC) counts as a clinically useful prognostic marker for predicting recurrence outcomes of early-stage (ES) non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT).

Methods And Materials: A cohort of 421 NSCLC patients was used to train a DL model for gleaning informative imaging features from computed tomography (CT) data. The learned imaging features were optimized on a cohort of 98 ES-NSCLC patients treated with SBRT for predicting individual patient recurrence risks by building DL models on CT data and clinical measures.

Cell plasticity, senescence, and quiescence in cancer stem cells: Biological and therapeutic implications.

Cancer stem cells (CSCs) are a distinct population of cells within tumors with capabilities of self-renewal and tumorigenicity. CSCs play a pivotal role in cancer progression, metastasis, and relapse and tumor resistance to cytotoxic therapy. Emerging scientific evidence indicates that CSCs adopt several mechanisms, driven by cellular plasticity, senescence and quiescence, to maintain their self-renewal capability and to resist tumor microenvironmental stress and treatments.

Novel Treatment for Glioblastoma Delivered by a Radiation Responsive and Radiopaque Hydrogel.

Successful treatment of glioblastoma (GBM) is hampered by primary tumor recurrence after surgical resection and poor prognosis, despite adjuvant radiotherapy and chemotherapy. In search of improved outcomes for this disease, quisinostat appeared as a lead compound in drug screening. A delivery system was devised for this drug and to exploit current clinical methodology: an injectable hydrogel, loaded with both the quisinostat drug and radiopaque gold nanoparticles (AuNP) as contrast agent, that can release these payloads as a response to radiation.

Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40.

Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs.

Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.

Background And Aims: Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation.