Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Differential expression of small bowel TGFß1 and TGFß3 characterizes intestinal strictures in patients with fibrostenotic Crohn's disease.

Small bowel strictures remain a debilitating consequence of Crohn's disease and contribute to poor outcomes for patients. Recently, TGFß has been identified as an important driver of intestinal fibrosis. We studied the localization of TGFß isoforms in ileal strictures of patients with Crohn's disease using in situ hybridization to understand TGFß's role in stricture formation. The mucosa of strictures was characterized by higher TGFß1 while the stricture submucosa showed higher TGFß3 compared to normal ileum from patients without Crohn's disease (p = 0.02 and p = 0.044, respectively). We correlated these findings with single-cell transcriptomics which demonstrated that TGFß3 transcripts overall are very rare, which may partially explain why its role in intestinal fibrosis has remained unclear to date. There were no significant differences in fibroblast or B cell TGFß1 and/or TGFß3 expression in inflamed vs. noninflamed ileum. We discuss the implications of these findings for therapeutic development strategies to treat patients with fibrostenotic Crohn's disease.

Accuracy of artificial intelligence-assisted growth prediction in skeletal Class I preadolescent patients using serial lateral cephalograms for a 2-year growth interval.

OBJECTIVE: To investigate the accuracy of artificial intelligence-assisted growth prediction using a convolutional neural network (CNN) algorithm and longitudinal lateral cephalograms (Lat-cephs). MATERIALS AND METHODS: A total of 198 Japanese preadolescent children, who had skeletal Class I malocclusion and whose Lat-cephs were available at age 8 years (T0) and 10 years (T1), were allocated into the training, validation, and test phases (n = 161, n = 17, n = 20). Orthodontists and the CNN model identified 28 hard-tissue landmarks (HTL) and 19 soft-tissue landmarks (STL). The mean prediction error values were defined as 'excellent,' 'very good,' 'good,' 'acceptable,' and 'unsatisfactory' (criteria: 0.5 mm, 1.0 mm, 1.5 mm, and 2.0 mm, respectively). The degree of accurate prediction percentage (APP) was defined as 'very high,' 'high,' 'medium,' and 'low' (criteria: 90%, 70%, and 50%, respectively) according to the percentage of subjects that showed the error range within 1.5 mm. RESULTS: All HTLs showed acceptable-to-excellent mean PE values, while the STLs Pog', Gn', and Me' showed unsatisfactory values, and the rest showed good-to-acceptable values. Regarding the degree of APP, HTLs Ba, ramus posterior, Pm, Pog, B-point, Me, and mandibular first molar root apex exhibited low APPs. The STLs labrale superius, lower embrasure, lower lip, point of lower profile, B', Pog,' Gn' and Me' also exhibited low APPs. The remainder of HTLs and STLs showed medium-to-very high APPs. CONCLUSION: Despite the possibility of using the CNN model to predict growth, further studies are needed to improve the prediction accuracy in HTLs and STLs of the chin area.

Exploring the cause of reduced production responses to feeding corn dried distillers' grains in lactating dairy cows.

An experiment was conducted to identify the factors that cause reduced production of cows fed a diet with high corn distiller's grains with solubles (DDGS). We hypothesized that the factors could be high S content in DDGS which may directly (S toxicity) or indirectly [dietary cation-anion difference (DCAD)] cause reduced production. We also hypothesized that high polyunsaturated fatty acids (PUFA) in DDGS could be another major factor. In a randomized complete block design, 60 lactating cows (15 primiparous and 45 multiparious; average ± SD at the beginning of the trial: milk yield, 44.0 ± 6.9 kg/d; DIM, 123 ± 50; BW, 672 ± 82 kg) were blocked and cows in each block were randomly assigned to one of the following treatments: SBM [4.7% fatty acids (FA), 0.22% S, and 178 mEq/kg DM of DCAD], a diet containing soybean meal as the main protein source; DG, SBM replacing mainly soybean byproducts and supplemental fat with DG at 30% dietary DM (4.7% FA, 0.44% S, and 42 mEq/kg DM of DCAD); SBM+S, SBM with sodium bisulfate for additional dietary S (4.8% FA, 0.37% S, and 198 mEq/kg DM of DCAD); SBM+CO, SBM with corn oil (4.7% FA, 0.23%, and 165 mEq/kg DM of DCAD); and DG+DCAD, DG with increased DCAD (4.7% FA, 0.40% S, and 330 mEq/kg DM of DCAD). Due to the limited tie stalls, the blocks of 1 to 6 started the experiment first as phase 1 and the rest of the blocks as phase 2 started the experiment after phase 1. All cows were fed the SBM diet for 10 d as a covariate period followed by the experimental period for 35 d. Data were analyzed using the PROC MIXED of SAS, block and phase were random effects and treatments, repeated wk, and interaction were fixed effects. There was an interaction of wk by treatment for DMI. While milk yield did not change, milk fat concentration tended to decrease (2.78 vs. 3.34%) for DG compared with SBM. Dry matter, OM, NDF, and CP digestibilities were lower when cows were fed the DG diet compared with SBM. Additionally, cows fed DG had lower blood concentrations of HCO3-, base excess, and tCO2 compared with SBM. The SBM+S diet did not affect production, nutrient digestibility, or blood parameters when compared with SBM. The SBM+CO diet decreased milk fat concentration and yield compared with SBM. The DG+DCAD diet tended to increase milk fat yield and concentration (1.24 vs. 1.47 kg/d; 2.78 vs. 3.37%) and increased ECM (40.9 vs. 45.1 kg/d) compared with DG but did not improve nutrient digestibility. However, blood HCO3-, base excess, and tCO2 were greater for DG+DCAD compared with DG. In conclusion, the indirect role of S-, altering DCAD, along with the high PUFA content in DDGS appears to be the factors causing reduced production responses to a high DDGS diet. Increasing DCAD to 300 mEq/kg DM in a high DDGS diet can be a feeding strategy to alleviate the reduced production responses.

Search for Boosted Dark Matter in COSINE-100.

We search for energetic electron recoil signals induced by boosted dark matter (BDM) from the galactic center using the COSINE-100 array of NaI(Tl) crystal detectors at the Yangyang Underground Laboratory. The signal would be an excess of events with energies above 4 MeV over the well-understood background. Because no excess of events are observed in a 97.7 kg·yr exposure, we set limits on BDM interactions under a variety of hypotheses. Notably, we explored the dark photon parameter space, leading to competitive limits compared to direct dark photon search experiments, particularly for dark photon masses below 4 MeV and considering the invisible decay mode. Furthermore, by comparing our results with a previous BDM search conducted by the Super-Kamionkande experiment, we found that the COSINE-100 detector has advantages in searching for low-mass dark matter. This analysis demonstrates the potential of the COSINE-100 detector to search for MeV electron recoil signals produced by the dark sector particle interactions.

A population physiologically-based pharmacokinetic model to characterize antibody disposition in pediatrics and evaluation of the model using infliximab.

AIMS: In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in paediatric patients, there is a need to develop systems PK models that integrate ontogeny-related changes in human physiological parameters. METHODS: A population-based physiological-based PK (PBPK) model to characterize antibody PK in paediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs. age and dose-exposure relationships for infliximab. RESULTS: By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two paediatric cohorts (n = 141, 4-19 years) reasonably well. Model simulations demonstrated that only 50% of children reached desired trough concentrations when receiving FDA-labelled dosing regimen for infliximab, suggesting that higher doses and/or more frequent dosing are needed to achieve target trough concentrations of this antibody. CONCLUSION: The paediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in paediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.

Healthcare utilisation for elderly people at the onset of the COVID-19 pandemic in South Korea.

BACKGROUND: At the onset of the coronavirus disease 2019 (COVID-19) pandemic, health care systems were severely disrupted in many countries and in particular, elderly people vulnerable to COVID-19 may have been reluctant to receive their medical treatment. METHODS: We conducted interrupted time series analyses (ITSA) using nationwide medical claim data between January 2020 and July 2020, with focus on different disease categories for the patients of 65 to 84-year-olds, i.e., acute upper respiratory infections (AURIs) vs. chronic diseases. RESULTS: AURIs and chronic diseases showed a sharp contrast with respect to the change in healthcare service utilisation. First, the utilisation rate for chronic diseases changed little whereas for AURIs it dropped by 20.4% year-over-year (yoy) at the onset of the pandemic (week 6, 2020). Second, as social distancing relaxed (week 17, 2020), the AURIs patients trended up and even reached to 7.8% above yoy whereas no significant change found for chronic diseases. CONCLUSIONS: The uninterrupted treatment for chronic diseases in contrast to the AURIs implies that the governmental and public responses to the pandemic outbreak worked for efficient healthcare provision to patients in needs of regular check-ups and treatment in the middle of an infectious disease crisis.

Entropic comparison of Landau-Zener and Demkov interactions in the phase space of a quadrupole billiard.

We investigate two types of avoided crossings in a chaotic billiard within the framework of information theory. The Shannon entropy in the phase space for the Landau-Zener interaction increases as the center of the avoided crossing is approached, whereas for the Demkov interaction, the Shannon entropy decreases as the center of avoided crossing is passed by with an increase in the deformation parameter. This feature can provide a new indicator for scar formation. In addition, it is found that the Fisher information of the Landau-Zener interaction is significantly larger than that of the Demkov interaction.

Altered distributions in circulating follicular helper and follicular regulatory T cells accountable for imbalanced cytokine production in multiple sclerosis.

Follicular T helper (Tfh) and regulatory (Tfr) cells are distinct subsets of CD4+ T lymphocytes, regulating humoral immune responses in the germinal center. It is widely accepted that dysregulated Tfh and Tfr cells are associated with autoimmunity. In this study, we evaluated the frequencies of circulating chemokine receptor (CXCR)5+ programmed cell death 1 (PD-1+ ) Tfh (cTfh) and CXCR5+ PD-1+ forkhead box protein 3 (FoxP3+ ) CD25+ Tfr (cTfr) cells, and their corresponding cytokines from the peripheral blood mononuclear cells of 28 patients with relapsing-remitting multiple sclerosis (MS) and 16 age- and sex-matched healthy controls (HC). Subsets of cTfh cells by Th1- and Th17-related surface markers (CXCR3 and CCR6) were also evaluated. We found that the frequency of cTfh cells was significantly higher in MS patients compared to that of HC. Conversely, the frequency of cTfr cells was lower in MS patients than that of HC. Interleukin (IL)-21-producing cTfh cells were significantly increased in MS patients, while IL-10-secreting cTfr cells were lower in MS patients compared to levels in HC. Among cTfh cells, cTfh17.1 cells were the major subtypes that were significantly increased in MS patients compared to HC, with the frequency of IL-21-secreting cells being the highest. These results suggest that an imbalanced distribution of cTfh and cTfr exist in MS patients, which contributes to the reciprocally altered IL-21 and IL-10 production.

Integrase strand transfer inhibitor treatment does not increase the incidence of immune reconstitution inflammatory syndrome in HIV-infected Koreans.

OBJECTIVES: Immune reconstitution inflammatory syndrome (IRIS) is a major concern when starting antiretroviral therapy (ART) in patients with advanced HIV infection. The aim of this study was to determine the incidence and risk factors of IRIS in HIV-infected Koreans initiating ART, and whether integrase strand transfer inhibitor (INSTI) treatment increases the risk of IRIS. METHODS: This retrospective analysis included adults living with HIV, seen at four university-affiliated hospitals in South Korea, who were naïve to ART and had a CD4 T-cell count < 200 cells/µL between January 2004 and May 2019. IRIS was determined through a medical record review within 6 months of ART initiation. Propensity score-matched case-control study between the non-INSTI and INSTI groups was performed. RESULTS: The study included 501 patients; 192 were assigned to the INSTI group, who started ART based on INSTIs as the initial treatment. There were opportunistic infections (OIs) in 253 (50.5%) cases before ART initiation. The three most common OIs were Pneumocystis jirovecii pneumonia, candidiasis and tuberculosis (TB). We identified 47 cases of IRIS; TB-IRIS was the most common type. The incidence of IRIS within 6 months of ART initiation was 9.4%, and there were no significant differences in baseline characteristics and incidence of IRIS between the matched groups. The risk factors for IRIS were pre-ART CD4 T-cell count (< 30 cells/µL), higher pre-ART viral load (≥ 75 000 copies/mL), and TB-OI. CONCLUSIONS: The incidence of IRIS was 9.4% in Korean HIV patients. The INSTI regimen was not related to IRIS occurrence.

Anterior resection syndrome: a randomized clinical trial of a 5-HT3 receptor antagonist (ramosetron) in male patients with rectal cancer.

BACKGROUND: No effective treatment exists for anterior resection syndrome (ARS) following sphincter-saving surgery for rectal cancer. This RCT assessed the safety and efficacy of a 5-HT3 receptor antagonist, ramosetron, for ARS. METHODS: A single-centre, randomized, controlled, open-label, parallel group trial was conducted. Male patients with ARS 1 month after rectal cancer surgery or ileostomy reversal were enrolled and randomly assigned (1 : 1) to 5 µg of ramosetron (Irribow®) daily or conservative treatment for 4 weeks. Low ARS (LARS) score was calculated after randomization and 4 weeks after treatment. The study was designed as a superiority test with a primary endpoint of the proportion of patients with major LARS between the groups. Primary outcome analysis was based on the modified intention-to-treat population. Safety was assessed by monitoring adverse events during the study. RESULTS: : A total of 100 patients were randomized to the ramosetron (49 patients) or conservative treatment group (51 patients). Two patients were excluded, and 48 and 50 patients were analysed in the ramosetron and control groups, respectively. The proportion of major LARS after 4 weeks was 58 per cent (28 of 48 patients) in the ramosetron group versus 82 per cent (41 of 50 patients) in the control group, with a difference of 23.7 per cent (95 per cent c.i. 5.58 to 39.98, P = 0.011). There were minor adverse events in five patients, which were hard stool, frequent stool or anal pain. These were not different between the two groups. There were no serious adverse events. CONCLUSION: : Ramosetron could be safe and feasible for male patients with ARS. TRIAL REGISTRATION NUMBER: NCT02869984 (http://www.clinicaltrials.gov).

CERKL is upregulated in cutaneous squamous cell carcinoma and maintains cellular sphingolipids and resistance to oxidative stress.

BACKGROUND: Ceramide kinase-like protein (CERKL) was originally described in retinal tissue. CERKL has been shown to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease retinitis pigmentosa. CERKL expression maintains cellular sphingolipids via an unknown mechanism. OBJECTIVES: To determine whether CERKL is expressed in epidermis and cutaneous squamous cell carcinoma (cSCC) and whether CERKL expression affects cSCC sphingolipid metabolism and susceptibility to oxidative stress. METHODS: CERKL expression was determined by RNA-Seq, quantitative polymerase chain reaction and immunohistochemistry. CERKL was knocked down in cSCC cells using small interfering RNA. Sphingolipid content was analysed by liquid chromatography-mass spectrometry. Oxidative stress was induced by treatment with H2 O2 , and apoptosis was measured using flow cytometry to determine annexin V binding. RESULTS: CERKL mRNA and protein are highly expressed in actinic keratosis and cSCC in comparison with normal epidermis. CERKL is also expressed in metabolically active epithelial cells in normal hair bulbs and sebaceous glands. CERKL knockdown in cultured cSCC cells reduces cellular sphingolipid content and enhances susceptibility to oxidative stress. CONCLUSIONS: These findings suggest that CERKL may be important in cSCC progression and could lead to novel strategies for prevention and treatment of cSCC.

Clinical Practice Survey of Repeat Endoscopy in Pediatric Inflammatory Bowel Disease in North America.

OBJECTIVES: Endoscopic remission has become a standard treatment target in inflammatory bowel disease (IBD). It is unclear how widely this practice has been adopted amongst pediatric gastroenterology providers. This study determines the frequency of repeat endoscopy in pediatric IBD and evaluates for predictive baseline characteristics of providers. METHODS: We developed a cross-sectional survey, which was distributed via 3 national email listservs to pediatric gastroenterology providers. We obtained baseline characteristics of respondents and assessed motivations and barriers for the practice of repeat endoscopy compared with none. RESULTS: Two hundred and thirty-eight unique respondents completed the online survey. Response rate was 11% (238 of 2300 possible participants). The majority practice in an academic setting (77%) and reported participation in ImproveCareNow (63%). Overall, 65% of respondents perform repeat endoscopy to assess for endoscopic remission in pediatric IBD as part of routine clinical practice. Fifty-six percent reported repeat endoscopy as individuals in the absence of a departmental protocol. "Symptoms are not sufficient to follow IBD patients" was reported by 82% of those who repeat endoscopy; conversely, "I perform endoscopy based on clinical, biomarker, and/or imaging trends" was reported by 81% of those who do not repeat endoscopy. The establishment of a pediatric-specific guideline was most commonly reported to change current practice, based on rank-order scoring. CONCLUSIONS: A majority of representative providers repeat endoscopy to assess for endoscopic remission in pediatric IBD. Fewer years in practice favored repeating endoscopy. The need for North American pediatric guidelines with pediatric-specific evidence to support the long-term benefits of endoscopic remission are highlighted in this study.

Radiomics-based model for predicting pathological complete response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

AIM: To develop and validate a radiomics-based model for predicting response to neoadjuvant chemotherapy (NAC) using baseline computed tomography (CT) images in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: A radiomics signature for predicting pathological complete response (pCR) was developed using radiomics features selected by a random forest classifier on baseline CT images, and imaging predictors were identified in the training set (87 patients). By incorporating imaging predictors and radiomics signature, an imaging-based model was constructed using multivariate logistic regression analysis and validated in an independent validation set consisting of 48 patients with CT from outside institutions. The performance and clinical usefulness of the imaging-based model for predicting pCR were evaluated using area under the receiver operating characteristic curve (AUC) and decision curve analysis. Using a cut-off determined in the training set, the positive likelihood ratios of the imaging-based model were calculated and compared with imaging and histological predictors. RESULTS: The radiomics signature was developed based on six stable radiomics features. An imaging-based model incorporating radiomics signature, tumour shape, tumour size, and clinical stage showed good performance for predicting pCR in both the training (AUC, 0.85; 95% confidence interval [CI], 0.78-0.93) and validation (AUC, 0.75; 95% CI, 0.60-0.86) sets, providing a larger net benefit in decision curve analysis. The imaging-based model showed a higher positive likelihood ratio (1.91) for pCR than imaging and histological predictors (1.33-1.63). CONCLUSIONS: The radiomics-based model using baseline CT images may predict the response of patients with MIBC to NAC.

Systemic contact dermatitis induced by Rhus allergens in Korea: exercising caution in the consumption of this nutritious food.

Systemic contact dermatitis (SCD) develops when a person who was previously sensitized to an allergen is exposed to the same allergen via the systemic route. In East Asia, the use of lacquer for polishing furniture is common and a part of the traditional culture. Contact exposure to tableware polished with Rhus lacquer may lead to sensitization. In Korea, SCD is commonly observed after systemic exposure to Rhus, a nutritious food item consumed because of the common belief of it improving the immune system. In this study, we reviewed the medical records of 21 Korean patients with SCD caused by Rhus ingestion. We found that the most significant epidemiological factor for SCD was the season of the year. Furthermore, 66.67% of the patients presented with leucocytosis and 23.81% showed increased liver enzyme levels. It is important to educate people on the risks associated with the systemic ingestion of Rhus.

Clinical features of subungual melanoma according to the extent of Hutchinson's nail sign: a retrospective single-centre study.

BACKGROUND: Hutchinson's nail sign (HS) is among the diagnostic criteria for subungual melanoma (SUM). However, there is minimal evidence supporting the overall clinical significance of HS in SUM. OBJECTIVES: To identify clinicopathological features of SUM according to the extent of HS. METHODS: Retrospective cohort study was performed with consecutive SUM patients at a single centre from January 2006 to December 2017. The extent of HS was defined by the number of affected nail folds (range 0-4). Comparison groups were organized as follows: patients with HS (affecting ≥1 nail folds) vs. without HS; patients with HS affecting ≥2 nail folds vs. HS affecting <2 nail folds; patients with HS affecting ≥3 nail folds vs. HS affecting <3 nail folds. Clinicopathological characteristics of SUM were compared between the groups. RESULTS: Sixty-one SUM patients were included. Forty-six (75.4%) exhibited HS; 22 (47.8%) on a toe and 24 (52.2%) on a finger. In multivariate analysis, nail destruction [hazard ratio (HR), 10.00; 95% confidence interval (CI), 2.61-38.30; P = 0.001] was significantly associated with the presence of HS and amputation was significantly associated with HS affecting ≥2 nail folds (HR, 4.75; 95% CI, 1.36-16.61; P = 0.015). High T stage (HR, 1.85; 95% CI, 1.20-2.85; P = 0.005, Fig. 2) was significantly associated with HS appearing in ≥3 nail folds. CONCLUSION: Besides its value of detecting SUM, HS provides useful clinical information. The number of nail folds exhibiting HS could be a useful clinical clue for planning therapeutic strategies for SUM.

Consensus statement from the international consensus meeting on post-traumatic cranioplasty.

BACKGROUND: Due to the lack of high-quality evidence which has hindered the development of evidence-based guidelines, there is a need to provide general guidance on cranioplasty (CP) following traumatic brain injury (TBI), as well as identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The international consensus meeting on post-traumatic CP was held during the International Conference on Recent Advances in Neurotraumatology (ICRAN), in Naples, Italy, in June 2018. This meeting was endorsed by the Neurotrauma Committee of the World Federation of Neurosurgical Societies (WFNS), the NIHR Global Health Research Group on Neurotrauma, and several other neurotrauma organizations. Discussions and voting were organized around 5 pre-specified themes: (1) indications and technique, (2) materials, (3) timing, (4) hydrocephalus, and (5) paediatric CP. RESULTS: The participants discussed published evidence on each topic and proposed consensus statements, which were subject to ratification using anonymous real-time voting. Statements required an agreement threshold of more than 70% for inclusion in the final recommendations. CONCLUSIONS: This document is the first set of practical consensus-based clinical recommendations on post-traumatic CP, focusing on timing, materials, complications, and surgical procedures. Future research directions are also presented.

Economic Studies Reinforce Efforts to Safeguard Specialty Crops in the United States.

Pathogen-tested foundation plant stocks are the cornerstone of sustainable specialty crop production. They provide the propagative units that are used to produce clean planting materials, which are essential as the first-line management option of diseases caused by graft-transmissible pathogens such as viruses, viroids, bacteria, and phytoplasmas. In the United States, efforts to produce, maintain, and distribute pathogen-tested propagative material of specialty crops are spearheaded by centers of the National Clean Plant Network (NCPN). Agricultural economists collaborated with plant pathologists, extension educators, specialty crop growers, and regulators to investigate the impacts of select diseases caused by graft-transmissible pathogens and to estimate the return on investments in NCPN centers. Economic studies have proven valuable to the NCPN in (i) incentivizing the use of clean planting material derived from pathogen-tested foundation plant stocks; (ii) documenting benefits of clean plant centers, which can outweigh operating costs by 10:1 to 150:1; (iii) aiding the development of disease management solutions that are not only ecologically driven but also profit maximizing; and (iv) disseminating integrated disease management recommendations that resonate with growers. Together, economic studies have reinforced efforts to safeguard specialty crops in the United States through the production and use of clean planting material.

Proteomic Discovery of Stool Protein Biomarkers for Distinguishing Pediatric Inflammatory Bowel Disease Flares.

Fecal calprotectin, the heterodimer of S100A8/S100A9, makes up ∼60% of neutrophil cytoplasmic protein content and is a canonical clinical biomarker of gut inflammation.1,2 Fecal calprotectin is commonly used to diagnose inflammatory bowel disease (IBD) and has an average sensitivity of 93% and specificity of 96%.1 For diagnosing pediatric IBD, calprotectin fecal tests have similar sensitivity (92%) but substantially less specificity (76%).1 Low specificity, especially in pediatric patients, means a high likelihood of false negative diagnoses, suggesting that a substantial number of active IBD cases remain undiagnosed and untreated. To improve on calprotectin as an effective IBD monitoring tool in pediatric populations, specificity must be increased. To develop an assay with higher specificity in pediatric patients, we identified a panel of multiple proteins that are present in both IBD flare and remission but have distinct abundance ranges between each condition. From a pilot cohort of 10 pediatric patients in states of either active disease or remission, we discovered and relatively quantified hundreds of stool proteins. Of these, our mass spectrometry-based study prioritized at least 5 that have potential to augment negative predictive power of mucosal-level inflammation alongside fecal biomarkers such as calprotectin.

ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer.

BACKGROUND: Many patients with metastatic non-small-cell lung cancer (mNSCLC) experience disease progression after first- and second-line treatment; more treatment options are required for these patients. ARCTIC, a phase III, randomized, open-label study, assessed durvalumab ± tremelimumab versus standard of care (SoC) as ≥ third-line treatment of mNSCLC. PATIENTS AND METHODS: ARCTIC comprised two independent sub-studies. Study A: 126 patients with ≥25% of tumor cells (TCs) expressing programmed cell death ligand-1 (PD-L1) were randomized (1 : 1) to durvalumab [up to 12 months 10 mg/kg every 2 weeks (q2w)] or SoC. Study B: 469 patients with PD-L1 TC <25% were randomized (3 : 2 : 2 : 1) to durvalumab + tremelimumab (12 weeks durvalumab 20 mg/kg + tremelimumab 1 mg/kg q4w then 34 weeks durvalumab 10 mg/kg q2w), SoC, durvalumab (up to 12 months 10 mg/kg q2w), or tremelimumab (24 weeks 10 mg/kg q4w then 24 weeks q12w). Primary end points: overall survival (OS) and progression-free survival (PFS) for durvalumab versus SoC (study A; descriptive only) and durvalumab + tremelimumab versus SoC (study B). RESULTS: Study A: median OS 11.7 (durvalumab) versus 6.8 (SoC) months {hazard ratio (HR) 0.63 [95% confidence interval (CI), 0.42-0.93]}; median PFS 3.8 (durvalumab) versus 2.2 (SoC) months [HR 0.71 (95% CI, 0.49-1.04)]. Study B: median OS 11.5 (durvalumab + tremelimumab) versus 8.7 (SoC) months [HR 0.80 (95% CI, 0.61-1.05); P = 0.109]. Median PFS of 3.5 months for both groups [HR 0.77 (95% CI, 0.59-1.01); P = 0.056]. Treatment-related grade 3/4 adverse events: 9.7% (durvalumab) and 44.4% (SoC; study A) and 22.0% (durvalumab + tremelimumab) and 36.4% (SoC; study B). CONCLUSIONS: In heavily pretreated patients with mNSCLC, durvalumab demonstrated clinically meaningful improvements in OS and PFS versus SoC (patients with PD-L1 TC ≥25%); numerical improvements in OS and PFS for durvalumab + tremelimumab versus SoC were observed (patients with PD-L1 TC <25%). Safety profiles were consistent with previous studies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02352948.