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The aim of this study is to describe the demographics and clinical features of patients with young onset (YO) CRC.A retrospective review of patients with CRC diagnosed between ages 20 and 49 years was evaluated at the Memorial Sloan Kettering Cancer Center from 1/2004 to 6/2019. We excluded those with a hereditary CRC syndrome, inflammatory bowel disease, or prior CRC diagnosis. Patient demographics; presenting symptoms; medical, surgical, and smoking history; family history of cancer; tumor characteristics; and pathology were obtained from the electronic medical record.We identified 3856 YO CRC patients (median age CRC diagnosis 43; 52.5% male). A total of 59.1% were overweight or obese (32.2% and 26.9%, respectively). Most (90.1%) had no family history of CRC in a first-degree relative; 56.3% of patients reported being never smokers; 5.2% had diabetes. The most common presenting symptoms were rectal bleeding (47.7%), abdominal pain/bloating (33.1%), and change in bowel habits (24.7%). The majority presented with left-sided cancers (77.3%), at late-stage disease (68.4% at stages 3 or 4).Most YO CRC patients presented with rectal bleeding or abdominal pain, left-sided cancers, and later-stage disease and had no family history of CRC in a first-degree relative. Over half were overweight and obese and were more likely to have never smoked. More data are needed to better understand YO CRC risk factors and to help identify high-risk populations who may benefit from earlier screening.

This study uses longitudinal data to follow a cohort ( N = 4,465) of all early childhood education teachers working in publicly funded, center-based settings in Louisiana over a 3-year period. We present the proportion of teachers still at their sites across six time points between 2016 and 2019, providing the first statewide, longitudinal estimates of within-year and multiyear retention. We find that less than 40% teachers in the fall of 2016 are still at their site by the fall of 2019. Turnover is particularly high among childcare teachers (compared to teachers at Head Start or school-based pre-kindergarten), teachers of toddlers, and teachers new to their sites. Policy implications are discussed.

Diffusion tensor imaging (DTI) literature on single-center studies contains conflicting results regarding acute effects of mild traumatic brain injury (mTBI) on white matter (WM) microstructure and the prognostic significance. This larger-scale multi-center DTI study aimed to determine how acute mTBI affects WM microstructure over time and how early WM changes affect long-term outcome. From Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI), a cohort study at 11 United States level 1 trauma centers, a total of 391 patients with acute mTBI ages 17 to 60 years were included and studied at two weeks and six months post-injury. Demographically matched friends or family of the participants were the control group (in/i = 148). Axial diffusivity (AD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were the measures of WM microstructure. The primary outcome was the Glasgow Outcome Scale Extended (GOSE) score of injury-related functional limitations across broad life domains at six months post-injury. The AD, MD, and RD were higher and FA was lower in mTBI versus friend control (FC) at both two weeks and six months post-injury throughout most major WM tracts of the cerebral hemispheres. In the mTBI group, AD and, to a lesser extent, MD decreased in WM from two weeks to six months post-injury. At two weeks post-injury, global WM AD and MD were both independently associated with six-month incomplete recovery (GOSElt;8 vs = 8) even after accounting for demographic, clinical, and other imaging factors. DTI provides reliable imaging biomarkers of dynamic WM microstructural changes after mTBI that have utility for patient selection and treatment response in clinical trials. Continued technological advances in the sensitivity, specificity, and precision of diffusion magnetic resonance imaging hold promise for routine clinical application in mTBI.

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Supplementary Figure S1 shows Correlation of IL-8 expression with overall survival in multiple cancers.

Supplementary Figure legends shows Figure S1-S6 legends

Legends for Supplementary Figures S1-S19.

Supplementary Fig. S17. Representative immunohistochemistry showing intratumoral, peritumoral, and marginal tissue stained for IL-18 from patients.

Purpose:The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes.Experimental Design:A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status.Results:Twenty-six percent (26/100; 95% confidence interval, 18.4–35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002).Conclusions:When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

Supplementary Figures S1-S16, S18, and S19 and Supplementary Tables S1-S4. Supplementary Fig. S1. Stratification of patients based on IL-18 staining density in intratumoral and peritumoral tissue. Supplementary Fig. S2. Efficient fibrosis induction by carbon tetrachloride and slightly modulated fibrosis burden between WT and IL18R1-/- mice. Supplementary Fig. S3. Multiple cell types produce IL-18 and IL18R1 in HCC. Supplementary Fig. S4. Enhanced neutrophil-to-lymphocyte ratios and decreased circulating lymphocytes in tumor-bearing IL18R1-/- mice. Supplementary Fig. S5. NK and NKT cells in liver and tumor are not significantly different between WT and IL18R1-/- mice. Supplementary Fig. S6. Myeloid cell accumulation in liver and tumor are not significantly different between WT and IL18R1-/- mice. Supplementary Fig. S7. Quantification of NK and T-cell populations in WT and IL18R1-/- mice. Supplementary Fig. S8. Representative flow cytometry of T-cell populations in non-tumor liver, tumor, and spleen in WT and IL18R1-/- mice. Supplementary Fig. S9. Alternative tumor models yield similar skewing of T-cell populations in the tumor by loss of IL18R1. Supplementary Fig. S10. Slightly increased proportions of CD44+ T-cells in IL18R1-/- mice compared to WT. Supplementary Fig. S11. No significant changes in CD4+ CD25+ cells, CD4+ FoxP3+ cells, or CD4+ CD25+ FoxP3+ cells. Supplementary Fig. S12. Modestly decreased PD-1 in CD8+ T cells in IL18R1-/- mice compared with WT mice. Supplementary Fig. S13. Slight differences in cytokine production, no differences in granzyme production in T-cells between WT and IL18R1-/- mice. Supplementary Fig. S14. Representative flow cytometry of differentiation and cytokine production of CD4+ T-cells from WT and IL18R1-/- mice. Supplementary Fig. S15. Representative flow cytometry of WT and IL18R1-/- CD8+ T-cell survival and proliferation upon reactivation and stimulation. Supplementary Fig. S16. Tumor-infiltrating NK cells have altered cytokine and transcription factor production between WT and IL18R1-/- mice. Supplementary Supplementary Fig. S18. Differences in IL-18 staining density between intratumoral and peritumoral tissue are more closely linked to peritumoral staining density. Supplementary Fig. S19. No difference in survival based on expression of IL18R1 in patient samples. Supplementary Table S1. Antibodies, Dyes, Stains, and Recombinant Proteins Used. Supplementary Table S2. qPCR Primers and shRNAs Used. Supplementary Table S3. Correlations between Patient Characteristics and Phenotypes and IL-18 Staining Density in Our 138 Patient Cohort. Supplementary Table S4. Average Density of Intratumoral and Peritumoral IL-18 Staining in Our 138 Patient Cohort.

Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression. In this study, we used tissue specimens from hepatocellular carcinoma patients and clinically relevant mouse models of hepatocellular carcinoma to evaluate IL18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity, and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL18 in tumor tissue versus nontumor tissue were more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL18 in established hepatocellular carcinoma and provide a mechanistic explanation for the complex relationship between its expression pattern and hepatocellular carcinoma prognosis. Cancer Res; 76(8); 2394–405. ©2016 AACR.

Hepatitis B–associated hepatocellular carcinoma (HCC) is often accompanied by severe vascular invasion and portal vein tumor thrombus, leading to a poor prognosis. However, the underlying mechanism of this disease remains obscure. In this study, we demonstrate that the hepatitis B virus (HBV)–encoded gene HBx induces high IL8 production through MEK–ERK signal activation, leading to enhanced endothelial permeability to facilitate tumor vascular invasion. In a vascular metastatic model using a tail vein injection in a transgenic mouse with selective expression of human CXCR1 in the endothelium, activation of the IL8–CXCR1 cascade by overexpression of IL8 in tumor cells dramatically enhanced liver metastasis. Mechanistically, IL8 selectively induced GARP-latent-TGFβ in liver sinusoidal endothelial cells and subsequently provoked preferential regulatory T-cell polarization to suppress antitumor immunity. Collectively, these findings reveal a hepatitis B–associated IL8–CXCR1 signaling axis that mediates vascular invasion and local microenvironmental immune escape of HCC to induce intrahepatic metastasis, which may serve as potential therapeutic targets for HBV-associated HCC.Significance:This study identifies a hepatitis B–induced IL8/CXCR1/TGFβ signaling cascade that suppresses antitumor immunity and enhances metastasis in hepatocellular carcinoma, providing new potential targets for therapeutic intervention.

Supplemental Table 1: Clinical Characteristics, Treatment, and Recurrence Rates of of Patients with Stage II SBA Supplemental Table 2. Germline variants among SBA patients

More detailed descriptions of patients and experimental protocols.

Background & aims Regulatory T cell (Treg) depletion increases antitumor immunity. However, severe autoimmunity can occur following systemic loss of Tregs, which could be avoided by selectively depleting intratumoral Tregs. Herein, we aimed to investigate the role of tumor-infiltrating CCR4+ Tregs in hepatocellular carcinoma (HCC) and to provide a potential target strategy for immunotherapy. Methods CCR4+ Tregs were analyzed by flow cytometry in murine models and clinical samples. The function of tumor-infiltrating and induced CCR4+ Tregs was interrogated by genetic and epigenetic approaches. To block CCR4+ Treg chemotaxis, we developed an N-terminus recombinant protein of CCR4 (N-CCR4-Fc) as a neutralizing pseudo-receptor that effectively bound to its ligand CCL22. The efficacy of CCR4 antagonism as an immunotherapeutic agent was evaluated by tumor weights, growth kinetics and survival curves. Results CCR4+ Tregs were the predominant type of Tregs recruited to hepatitis B-associated HCC (HBV+ HCC), correlating with sorafenib resistance and HBV load titers. Compared with CCR4- Tregs, CCR4+ Tregs exhibited increased IL-10 and IL-35 expression, and enhanced functionality in suppressing CD8+ T cells. CCR4+ Tregs also displayed PD-1+TCF1+ stem-like properties. ATAC-seq data revealed substantial chromatin remodeling between tumor-infiltrating Tregs (TIL-Tregs) and induced Tregs, suggesting that long-term chromatin reprogramming accounted for the acquisition of enhanced immunosuppressive stem-like specificity by CCR4+ TIL-Tregs. Treatment with a CCR4 antagonist or N-CCR4-Fc blocked intratumoral Treg accumulation, overcame sorafenib resistance, and sensitized tumors to PD-1 checkpoint blockade. Conclusions Intratumoral stem-like CCR4+ Tregs orchestrated immunosuppressive resource cells in the tumor microenvironment. CCR4 could be targeted to enhance antitumor immunity by specifically blocking infiltration of Tregs into the tumor microenvironment and inhibiting maintenance of the TIL-Treg pool. Lay summary Targeting regulatory T cells is a promising approach in cancer immunotherapy; however, severe autoimmunity can occur following systemic regulatory T cell loss. This could be avoided by selectively depleting intratumoral regulatory T cells. Herein, targeting intratumoral stem-like CCR4+ regulatory T cells helped to overcome sorafenib resistance and sensitize tumors to immune checkpoint blockade in mouse models of liver cancer. This approach could have wide clinical applicability.

Purpose This study explored the clinicopathologic outcomes of rectal tumor morphological descriptors used in a synoptic rectal MRI reporting template and determined that prognostic differences were observed. Methods This retrospective study was conducted at a comprehensive cancer center. Fifty patients with rectal tumors for whom the synoptic descriptor “polypoid” was chosen by three experienced radiologists were compared with ninety comparator patients with “partially circumferential” and “circumferential” rectal tumors. Two radiologists re-evaluated all cases. The outcome measures were agreement among two re-interpreting radiologists, clinical T staging with MRI (mrT) and descriptive nodal features, and degrees of wall attachment of tumors (on MRI) compared with pathological (p) T and N stage when available. Results Re-evaluation by two radiologists showed moderate to excellent agreement in tumor morphology, presence of a pedicle, and degree of wall attachment (k = 0.41–0.76) and excellent agreement on lymph node presence and size (ICC = 0.83–0.91). Statistically significant lower mrT stage was noted for polypoid morphology, wherein 98% were mrT1/2, while only 7% and 2% of partially circumferential and circumferential tumors respectively were mrT1/2. Pathologic T and N stages among the three morphologies also differed significantly, with only 14% of polypoid cases higher than stage pT2 compared to 48% of partially circumferential cases and 60% of circumferential cases. Conclusion Using a “polypoid” morphology in rectal cancer MRI synoptic reports revealed a seemingly distinct phenotype with lower clinical and pathologic T and N stages when compared with alternative available descriptors. Precis “Polypoid” morphology in rectal cancer confers a lower clinical and pathologic T and N stage and may be useful in determining whether to proceed with surgery versus neoadjuvant treatment.

PURPOSE NTHL1 and MSH3 have been implicated as autosomal recessive cancer predisposition genes. Although individuals with biallelic NTHL1 and MSH3 pathogenic variants (PVs) have increased cancer and polyposis risk, risks for monoallelic carriers are uncertain. We sought to assess the prevalence and characterize NTHL1 and MSH3 from a large pan-cancer patient population. MATERIALS AND METHODS Patients with pan-cancer (n = 11,081) underwent matched tumor-normal sequencing with consent for germline analysis. Medical records and tumors were reviewed and analyzed. Prevalence of PVs was compared with reference controls (Genome Aggregation Database). RESULTS NTHL1-PVs were identified in 40 patients including 39 monoallelic carriers (39/11,081 = 0.35%) and one with biallelic variants (1/11,081 = 0.009%) and a diagnosis of isolated early-onset breast cancer. NTHL1-associated mutational signature 30 was identified in the tumors of the biallelic patient and two carriers. Colonic polyposis was not identified in any NTHL1 patient. MSH3-PVs were identified in 13 patients, including 12 monoallelic carriers (12/11,081 = 0.11%) and one with biallelic MSH3 variants (1/11,081 = 0.009%) and diagnoses of later-onset cancers, attenuated polyposis, and abnormal MSH3-protein expression. Of the 12 MSH3 carriers, two had early-onset cancer diagnoses with tumor loss of heterozygosity of the wild-type MSH3 allele. Ancestry-specific burden tests demonstrated that NTHL1 and MSH3 prevalence was not significantly different in this pan-cancer population versus controls. CONCLUSION NTHL1 and MSH3 germline alterations were not enriched in this pan-cancer patient population. However, tumor-specific findings, such as mutational signature 30 and loss of heterozygosity of the wild-type allele, suggest the potential contribution of monoallelic variants to tumorigenesis in a subset of patients.

BACKGROUND AND AIMS: Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer and is associated with an increased lifetime risk of gastric and duodenal cancers of 8–16% and 7% respectively, therefore, we aim to describe an esophagogastroduodenoscopy (EGD) surveillance program for upper gastrointestinal (GI) precursor lesions and cancer in LS patients. METHODS: Patients who either had positive genetic testing or met clinical criteria for LS who had a surveillance EGD at our institution from 1996 to 2017 were identified. Patients were included if they had at least two EGDs or an upper GI cancer detected on the first surveillance EGD. EGD and pathology reports were extracted manually. RESULTS: Our cohort included 247 patients with a mean age of 47.1 years (SD 12.6) at first EGD. Patients had a mean of 3.5 EGDs (range 1–16). Mean duration of follow-up was 5.7 years. Average interval between EGDs was 2.3 years. Surveillance EGD detected precursor lesions in 8 (3.2%) patients, two (0.8%) gastric cancers and two (0.8%) duodenal cancers. Two interval cancers were diagnosed: a duodenal adenocarcinoma was detected 2 years, 8 months after prior EGD and a jejunal adenocarcinoma was detected 1 year, 9 months after prior EGD. CONCLUSIONS: Our data suggest that surveillance EGD is a useful tool to help detect precancerous and cancerous upper GI lesions in LS patients. To our knowledge, this is the first study to examine a program of surveillance EGDs in LS patients. More data are needed to determine the appropriate surveillance interval.

OBJECTIVE: To examine the association between hearing impairment and cognitive function after traumatic brain injury (TBI). SETTING: A total of 18 Level I trauma centers throughout the United States in the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. PARTICIPANTS: From February 2014 to June 2018, 2,697 participants with TBI were enrolled in TRACK-TBI. Key eligibility criteria included external force trauma to the head, presentation to a participating Level I trauma center, and receipt of a clinically indicated head computerized tomography (CT) scan within 24 hours of injury. A total of 1,267 participants were analyzed in the study, with 216 participants with hearing impairment and 1,051 participants without hearing impairment. Those with missing or unknown hearing status or cognitive assessment were excluded from analysis. DESIGN: Prospective, observational cohort study. MAIN MEASURES: Hearing impairment at 2 weeks post-TBI was based on self-report. Participants who indicated worse hearing in one or both ears were defined as having hearing impairment, while those who denied worse hearing in either ear were defined as not having hearing impairment and served as the reference group. Cognitive outcomes at 6 months post-TBI included executive functioning and processing speed, as measured by the Trail Making Test (TMT) B/A and the Wechsler Adult Intelligence Scale, Fourth Edition, Processing Speed Index Subscale (WAIS-IV PSI), respectively. RESULTS: TBI-related hearing impairment had a small but significantly greater TMT B/A ratio than without TBI-related hearing impairment (mean difference (B) = 0.25; 95% CI = 0.07 – 0.43; p = 0.005). No significant mean differences on WAIS-IV PSI scores were found between participants with and without TBI-related hearing impairment (B = 0.36; 95% CI = −2.07 – 2.60; p = 0.825). CONCLUSION: We conclude that TBI-related hearing impairment at 6 months post-injury was significantly associated with worse executive functioning but not cognitive processing speed.

The National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH-NINDS) Traumatic Brain Injury (TBI) Imaging Common Data Elements (CDEs) are standardized definitions for pathological intracranial lesions based on their appearance on neuroimaging studies. The NIH-NINDS TBI Imaging CDEs were designed to be as consistent as possible with the U.S. Food and Drug Administration (FDA) definition of biomarkers as "an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention." However, the FDA qualification process for biomarkers requires proof of reliable biomarker test measurements. We determined the interrater reliability of TBI Imaging CDEs on subacute brain magnetic resonance imaging (MRI) performed on 517 mild TBI patients presenting to 11 U.S. level 1 trauma centers. Three U.S. board-certified neuroradiologists independently evaluated brain MRI performed 2 weeks post-injury for the following CDEs: traumatic axonal injury (TAI), diffuse axonal injury (DAI), and brain contusion. We found very high interrater agreement for brain contusion, with prevalence- and bias-adjusted kappa (PABAK) values for pairs of readers from 0.92 [95% confidence interval, 0.88-0.95] to 0.94 [0.90-0.96]. We found intermediate agreement for TAI and DAI, with PABAK values of 0.74-0.78 [0.70-0.82]. The near-perfect agreement for subacute brain contusion is likely attributable to the high conspicuity and distinctive appearance of these lesions on T1-weighted images. Interrater agreement for TAI and DAI was lower, because signal void in small vascular structures, and artifactual foci of signal void, can be difficult to distinguish from the punctate round or linear areas of slight hemorrhage that are a common hallmark of TAI/DAI on MRI.

Radiation therapy (RT) in combination with an immune checkpoint inhibitor (ICI) represents a promising regimen for non-small cell lung cancer (NSCLC); however, the underlying mechanisms are poorly characterized. We identified a specific dose of RT that conferred tumor regression and improved survival in NSCLC models when combined with ICIs. The immune-modulating functions of RT were ascribed to activated lung-resident Scgb1a1+ club cells. Notably, mice with club-cell-specific knockout of synaptosome-associated protein 23 failed to benefit from the combination treatment, indicating a pivotal role of club cell secretome. We identified eight club cell secretory proteins that inhibited immunosuppressive myeloid cells, reduced pro-tumor inflammation and enhanced antitumor immunity. Notably, CC10, a member of club cell secretome, was increased in plasma of patients with NSCLC responding to the combination therapy. By revealing an immunoregulatory role of club cells, our studies have the potential to guide future clinical trials of ICIs in NSCLC. Mittal and colleagues investigate the mechanisms underlying the therapeutic effects of radiation therapy in combination with checkpoint blockade, finding a role for activated lung-resident secretory club cells in modulating antitumor immune responses.

Adult patients with mild traumatic brain injury (mTBI) exhibit distinct phenotypes of emotional and cognitive functioning identified by latent profile analysis of clinical neuropsychological assessments. When discerned early after injury, these latent clinical profiles have been found to improve prediction of long-term outcomes from mTBI. The present study hypothesized that white matter (WM) microstructure is better preserved in an emotionally resilient (ER) mTBI phenotype compared with a neuropsychiatrically distressed (ND) mTBI phenotype.The present study used diffusion MRI to investigate and compare WM microstructure in major association, projection, and commissural tracts between the two phenotypes and over time. Diffusion MR images from 172 mTBI patients were analyzed to compute individual diffusion tensor imaging (DTI) maps at 2 weeks and 6 months postinjury.By comparing the DTI parameters between the two phenotypes at global, regional, and voxel levels, the present study showed that the ER patients have higher axial diffusivity (AD) compared to their ND counterparts early after mTBI. Longitudinal analysis revealed greater compromise of WM microstructure in ND patients, with greater decrease of global AD and more widespread decrease of regional AD during the first 6 months after injury compared to their ER counterparts.These results provide neuroimaging evidence of WM microstructural differences underpinning mTBI phenotypes identified from neuropsychological assessments and show differing longitudinal trajectories of these biological effects. These findings suggest diffusion MRI can provide short- and long-term imaging biomarkers of resilience.

The Glasgow Outcome Scale (GOS) in its original or extended (GOSE) form is the most widely used assessment of global disability in traumatic brain injury (TBI) research. Several publications have reported concerns about assessor scoring inconsistencies, but without documentation of contributing factors. We reviewed 6801 GOSE assessments collected longitudinally, across 18 sites in the 5-year, observational Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. We recorded error rates (i.e., corrections to a section or an overall rating) based on site assessor documentation and categorized scoring issues, which then informed further training. In cohort 1 (n = 1261; February 2014 to May 2016), 24% of GOSEs had errors identified by central review. In cohort 2 (n = 1130; June 2016 to July 2018), acquired after curation of cohort 1 data, feedback, and further training of site assessors, the error rate was reduced to 10%. GOSE sections associated with the most frequent interpretation and scoring difficulties included whether current functioning represented a change from pre-injury (466 corrected ratings in cohort 1; 62 in cohort 2), defining dependency in the home and community (163 corrections in cohort 1; three in cohort 2) and return to work/school (72 corrections in cohort 1; 35 in cohort 2). These results highlight the importance of central review in improving consistency across sites and over time. Establishing clear scoring criteria, coupled with ongoing guidance and feedback to data collectors, is essential to avoid scoring errors and resultant misclassification, which carry potential to result in "failure" of clinical trials that rely on the GOSE as their primary outcome measure.

Food insecurity—lack of access to sufficient food for an active and healthy lifestyle—affects more than 10 million children in the United States. Ample research links food insecurity to hampered child physical, cognitive, and social-emotional development and provides insights for policy. After introducing food insecurity and its measurement, this article summarizes what is known about the effects of food insecurity on child development. It then considers how food insecurity harms children and explores both direct pathways through child health and indirect pathways through parenting and parent well-being. Finally, after reviewing existing policy for reducing food insecurity, we provide suggestions for new policy and policy-targeted research.

Background We previously reported the effectiveness of vedolizumab (VDZ) to induce remission in children with CD and UC enrolled in the prospective,multicenter VEDOKIDS study.In this extended analysis,we aimed to explore the effectiveness and safety of VDZ to maintain remission through week 30 Methods Children with CD or UC commenced on VDZ at any stage of the disease were followed at baseline and 2, 6, 14 and 30 weeks thereafter.Explicit demographic,clinical and safety data were prospectively recorded.The primary outcome was steroid-and EEN-free clinical remission (SFR) at 30 weeks,analyzed under the ITT principle with non-response imputation.Response was defined as change of ≥ 20 points in PUCAI or >20 points in wPCDAI and clinical remission as PUCAI Results A total of 142 children were enrolled (65 [46%] CD,77 [54%] UC;Table).At the end of the induction period,the rates of response were 75% in UC vs 64% in CD (p=0.2),of remission 52% vs 38% (p=0.1),and of SFR 47% vs 32% (p=0.08),respectively.At week 30,SFR rates were 47% in UC and 34% in CD (p=0.1);outcomes were also numerically higher in UC,but without statistical significance(Figure) Response to induction therapy predicted week 30 remission.Of the responders,19 (59%) children with CD and 31 (60%) with UC achieved SFR at week 30,while the corresponding figures for those not achieving response were 3 (12%; p=0.004) in CD and 5 (29%; p=0.03) in UC.Similarly,in multivariable model,response to induction treatment was highly associated with SFR at week 30,in both CD (OR 11.2 [95%CI 2.3-73]) and UC (OR 4.8 [95%CI 1.4-19]).Of the 22 patients who were responders but not remitters at week 14,four eventually achieved SFR at week 30 (1/10 [10%] in CD and 3/12 [25%] in UC) By week 30,159 AE's were reported by 72 children including one case of Hodgkin's lymphoma (VDZ was resumed after completing the chemotherapy);the patient was never exposed to thiopurines.No cases of progressive multifocal leukoencephalopathy or deaths were reported.Thirty-six AEs in 23 (16%) children were classified as possibly related to VDZ,11 of which (31%) were moderate and the others mild.Four children (1.4%) discontinued treatment due to AEs (one due to infusion reaction,one leukocytoclastic vasculitis,one azotemia and one due to fever and malaise Conclusion In this prospective multicenter study,VDZ was effective for maintaining remission in children with CD, and more so in UC.Contraty to common notions,children with CD not achieving complete remission by week 14 had a very low likelihood of entering remission thereafter.Safety profile was generally good except for one lymphoma case with questionable relation to VDZ