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European journal of cancer 160, 80-91 (2022). doi:10.1016/j.ejca.2021.10.007, Published by Elsevier, Amsterdam [u.a.]

Future climate scenarios are predicting considerable threats to sustainable maize production in arid and semi-arid regions. These adverse impacts can be minimized by adopting modern agricultural tools to assess and develop successful adaptation practices. A multi-model approach (climate and crop) was used to assess the impacts and uncertainties of climate change on maize crop. An extensive field study was conducted to explore the temporal thermal variations on maize hybrids grown at farmer’s fields for ten sowing dates during two consecutive growing years. Data about phenology, morphology, biomass development, and yield were recorded by adopting standard procedures and protocols. The CSM-CERES, APSIM, and CSM-IXIM-Maize models were calibrated and evaluated. Five GCMs among 29 were selected based on classification into different groups and uncertainty to predict climatic changes in the future. The results predicted that there would be a rise in temperature (1.57–3.29 °C) during the maize growing season in five General Circulation Models (GCMs) by using RCP 8.5 scenarios for the mid-century (2040–2069) as compared with the baseline (1980–2015). The CERES-Maize and APSIM-Maize model showed lower root mean square error values (2.78 and 5.41), higher d-index (0.85 and 0.87) along reliable R2 (0.89 and 0.89), respectively for days to anthesis and maturity, while the CSM-IXIM-Maize model performed well for growth parameters (leaf area index, total dry matter) and yield with reasonably good statistical indices. The CSM-IXIM-Maize model performed well for all hybrids during both years whereas climate models, NorESM1-M and IPSL-CM5A-MR, showed less uncertain results for climate change impacts. Maize models along GCMs predicted a reduction in yield (8–55%) than baseline. Maize crop may face a high yield decline that could be overcome by modifying the sowing dates and fertilizer (fertigation) and heat and drought-tolerant hybrids.

Background At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict coronavirus disease 2019 (COVID-19) illness. However, the results are not conclusive, as critical illness can drastically alter a patient’s microbiome through multiple confounders. Methods To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multicenter, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate, and severe COVID-19 (n = 322 participants). Results In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features. Conclusions In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.

Context Peer providers with lived experiences of mental health and substance use are a growing component of the workforce responsible for the prevention and treatment of behavioral health disorders. This systematic literature review aims to better define the roles of peers and their unique contributions to behavioral health care. Evidence acquisition Researchers searched MEDLINE, CINAHL Complete, PsycINFO, Cochrane Central, and Scopus databases for studies published between January 1, 2013 and April 3, 2020. Studies were included if they (1) were experimental or observational studies, (2) included an adult population of people with a behavioral health disorder, and (3) used paid peer providers in addition to traditional behavioral health services. Researchers extracted sample demographics, intervention characteristics, outcome data, and significant associations from studies that met inclusion criteria and assessed the trends in these data in May 2020. Evidence synthesis A total of 23 articles assessing peer-provided services were included. Peers were employed most frequently in mental healthcare roles in the Department of Veterans Affairs, hospital, and community health facilities. A total of 14 studies observed significant clinical improvements in participants’ social functioning, quality of life, patient activation, and behavioral health. A majority of studies involved the supervision of peers and required peers to have completed training in service delivery. Conclusions Peers are effective providers of behavioral health treatment and relapse prevention services who encourage recovery through resilience building, empowerment, and self-advocacy. There remains a need for more evidence-based interventions on the efficacy of peers in substance use disorder treatment and the impact of formalized certification and training opportunities.

To develop a new digital biomarker based on the analysis of primary tumour tissue by a convolutional neural network (CNN) to predict lymph node metastasis (LNM) in a cohort matched for already established risk factors.Haematoxylin and eosin (HE) stained primary tumour slides from 218 patients (102 N+; 116 N0), matched for Gleason score, tumour size, venous invasion, perineural invasion and age, who underwent radical prostatectomy were selected to train a CNN and evaluate its ability to predict LN status.With 10 models trained with the same data, a mean area under the receiver operating characteristic curve (AUROC) of 0.68 (95% confidence interval [CI] 0.678-0.682) and a mean balanced accuracy of 61.37% (95% CI 60.05-62.69%) was achieved. The mean sensitivity and specificity was 53.09% (95% CI 49.77-56.41%) and 69.65% (95% CI 68.21-71.1%), respectively. These results were confirmed via cross-validation. The probability score for LNM prediction was significantly higher on image sections from N+ samples (mean [SD] N+ probability score 0.58 [0.17] vs 0.47 [0.15] N0 probability score, P = 0.002). In multivariable analysis, the probability score of the CNN (odds ratio [OR] 1.04 per percentage probability, 95% CI 1.02-1.08; P = 0.04) and lymphovascular invasion (OR 11.73, 95% CI 3.96-35.7; P0.001) proved to be independent predictors for LNM.In our present study, CNN-based image analyses showed promising results as a potential novel low-cost method to extract relevant prognostic information directly from HE histology to predict the LN status of patients with prostate cancer. Our ubiquitously available technique might contribute to an improved LN status prediction.

Renal cell carcinoma (RCC) is the deadliest primary genitourinary malignancy typically associated with asymptomatic initial presentation and poorly predictable survival. Next to established risk factors, tumor microenvironment may alter metastatic capacity and immune landscape. Due to their high concentrations, sulfoglycolipids (sulfatides) were among the first well-described antigens in RCC that are associated with worse prognosis. As sulfatide detection in routine diagnostics is not possible, we aimed to test the prognostic value of its protein counterpart, sulfatide-producing enzyme Gal3ST1. We performed retrospective long-term follow up analysis of Gal3ST1 expression as prognostic risk factor in a representative RCC patient cohort. We observed differentially regulated Gal3ST1 expression in all RCC types, being significantly more associated with clear cell RCC than to chromophobe RCC (p = 0.001). Surprisingly, in contrast to published observations from in vitro models, we could not confirm an association between Gal3ST1 expression and a malignant clinical behaviour of the RCC. In our cohort, Gal3ST1 did not significantly influence progression-free survival (Hazard Ratio (HR): 1.7 95% CI (0.6–4.9), p = 0.327). Particularly after adjusting for histology, T-stage, N-status and M-status at baseline, we observed no independent prognostic effect (HR = 1.0 95% CI (0.3–3.3), p = 0.96). The analysis of Gal3ST1 mRNA expression in a TCGA dataset supported the results of our cohort. Thus, Gal3ST1 might help to differentiate between chromophobe RCC and other frequent RCC entities but—despite previously published data from cell culture models—does not qualify as a prognostic marker for RCC. Further investigation of regulatory mechanisms of sulfatide metabolism in human RCC microenvironment is necessary to understand the role of this quantitatively prominent glycosphingolipid in RCC progression.

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, with a 5-year survival rate as low as 9%. One factor complicating the management of pancreatic cancer is the lack of reliable tools for early diagnosis. While up to 50% of the adult population has been shown to develop precancerous pancreatic cysts, limited and insufficient approaches are currently available to determine whether a cyst is going to progress into pancreatic cancer. Recently, we used metabolomics approaches to identify candidate markers of disease progression in patients diagnosed with intraductal papillary mucinous neoplasms (IPMNs) undergoing pancreatic resection. Here we enrolled an independent cohort to verify the candidate markers from our previous study with orthogonal quantitative methods in plasma and cyst fluid from serous cystic neoplasm and IPMN (either low- or high-grade dysplasia or pancreatic ductal adenocarcinoma). We thus validated these markers with absolute quantitative methods through the auxilium of stable isotope-labelled internal standards in a new independent cohort. Finally, we identified novel markers of IPMN status and disease progression – including amino acids, carboxylic acids, conjugated bile acids, free and carnitine-conjugated fatty acids, purine oxidation products and TMAO. We show that the levels of these metabolites of potential bacterial origin correlated with the degree of bacterial enrichment in the cyst, as determined by 16S RNA. Overall, our findings are interesting per se, owing to the validation of previous markers and identification of novel small molecule signatures of IPMN and disease progression. In addition, our findings further fuel the provoking debate as to whether bacterial infections may represent an etiological contributor to the development and severity of the disease in pancreatic cancer, in like fashion to other cancers (e.g.,Helicobacter pyloriand gastric cancer).Key pointsWe identified and quantified novel markers of IPMN cyst status and pancreatic cancer disease progression – including amino acids, carboxylic acids, conjugated bile acids, free and carnitine-conjugated fatty acids, purine oxidation products and TMAO.We show that the levels of these metabolites of potential bacterial origin correlated with the degree of bacterial enrichment in the cyst, as determined by 16S RNA.

Die AG „Junge DGKJ“ der Deutschen Gesellschaft fur Kinder- und Jugendmedizin (DGKJ) hat 2019 eine Weiterbildungsumfrage mit insgesamt 1694 teilnehmenden Assistenzarzt*innen aus ganz Deutschland durchgefuhrt und anhand der Antworten das vorliegende Positionspapier zu Weiterbildungs- und Arbeitsbedingungen in der Padiatrie erstellt. Es schildert die bestehenden Probleme junger arztlicher Kolleg*innen und versucht Losungsvorschlage aufzuzeigen. Dabei gliedert es sich in 6 verschiedene Themenbereiche: steigende Patientenzahlen bei hohem Okonomisierungsdruck, zunehmende Arbeitsverdichtung wegen Durchfuhrung nichtarztlicher Tatigkeiten, Bedarf an flexiblen Teilzeitmodellen, notwendige Optimierung der Weiterbildung, Herausforderungen, die der hohe Frauenanteil in der Padiatrie mit sich bringt, sowie Problematik der steigenden Zahlen seelisch/psychisch belasteter Arzte. Als Fazit bedarf es der Erarbeitung funktionierender, moderner und den gesellschaftlichen Entwicklungen gerecht werdender Arbeits(zeit)-modelle, die eine langfristige qualitativ hochwertige medizinische Versorgung von Kindern und Jugendlichen in Deutschland durch gesundes medizinisches Personal und unter Berucksichtigung der optimalen Weiterbildung von Assistenzarzt*innen ermoglichen.

Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). In contrast to sporadic colorectal tumorigenesis, TP53 mutations occur early in the progression from inflamed colonic epithelium to dysplasia to CRC, and are sometimes readily detectable in inflamed, (yet) non-dysplastic mucosa. Here, we analyzed formalin-fixed paraffin-embedded tissue samples from 19 patients with long-standing UC (median 18 years, range 3 to 34) who had developed CRC as a consequence of chronic inflammation of the large bowel. We performed microsatellite instability testing, copy number analysis by array-based comparative genomic hybridization, mutation analysis by targeted next generation sequencing (48-gene panel) and TP53 immunostaining. The results were compared to The Cancer Genome Atlas (TCGA) data on sporadic CRC. All UC-CRC lesions in our cohort were microsatellite stable. Overall, genomic imbalances of UC-CRCs showed patterns of chromosomal aneuploidies characteristic for sporadic CRC with the exception of gains of chromosome arm 5p (12 of 23 UC-CRC, 52%), which are rare in sporadic CRCs from TCGA (21 of 144, 15%; FDR adjusted P = 0.006). UC-CRCs showed a predilection for TP53 alterations, which was the most frequently mutated gene in our cohort (20 of 23, 87%). Interestingly, spatially separated tumor lesions from individual patients tended to harbor distinct TP53 mutations. Similar to CRCs arising in a background of Crohn’s colitis, the genetic landscape of UC-CRCs was characterized by TP53 mutations and chromosomal aneuploidies including gains of chromosome arm 5p. Both alterations harbor the potential for early detection in precursor lesions, thus complementing morphologic diagnosis.

Background In recent studies, convolutional neural networks (CNNs) outperformed dermatologists in distinguishing dermoscopic images of melanoma and nevi. In these studies, dermatologists and artificial intelligence were considered as opponents. However, the combination of classifiers frequently yields superior results, both in machine learning and among humans. In this study, we investigated the potential benefit of combining human and artificial intelligence for skin cancer classification. Methods Using 11,444 dermoscopic images, which were divided into five diagnostic categories, novel deep learning techniques were used to train a single CNN. Then, both 112 dermatologists of 13 German university hospitals and the trained CNN independently classified a set of 300 biopsy-verified skin lesions into those five classes. Taking into account the certainty of the decisions, the two independently determined diagnoses were combined to a new classifier with the help of a gradient boosting method. The primary end-point of the study was the correct classification of the images into five designated categories, whereas the secondary end-point was the correct classification of lesions as either benign or malignant (binary classification). Findings Regarding the multiclass task, the combination of man and machine achieved an accuracy of 82.95%. This was 1.36% higher than the best of the two individual classifiers (81.59% achieved by the CNN). Owing to the class imbalance in the binary problem, sensitivity, but not accuracy, was examined and demonstrated to be superior (89%) to the best individual classifier (CNN with 86.1%). The specificity in the combined classifier decreased from 89.2% to 84%. However, at an equal sensitivity of 89%, the CNN achieved a specificity of only 81.5% Interpretation Our findings indicate that the combination of human and artificial intelligence achieves superior results over the independent results of both of these systems.

Recruiting participants with chronic medical conditions is time-consuming and expensive. Electronic medical record databases and patient portals may enable outreach to larger numbers of patients in comparison to face-to-face methods. We aimed to describe the yields, benefits, and limitations of recruitment strategies used for a randomized clinical trial of cognitive behavioral therapy for insomnia among patients with chronic stable heart failure (NCT02660385). We used multiple recruitment strategies including clinic-based recruitment, letters to patients identified from electronic databases, the patient portal, brochures and posters placed in clinics, presentations to heart failure support groups, and online advertising. We screened 10,291 medical records, enrolled 231 participants, and 195 participants completed baseline data collection. We enrolled 92 (23%) participants using clinic-based recruitment, 24 and 29 (6% and 10%) using letters to patients from two electronic databases, and 42 (55%) via the patient portal. Multiple recruitment strategies and flexibility are needed to achieve recruitment goals.

Background and purpose Providing evidence for radiotherapy (RT)-induced effects on cardiac implantable electric devices (CIEDs) with focus on flattening filter free-volumetric modulated arc therapy (FFF-VMAT) at 6 and 10 MV as well as 3D-conformal radiotherapy (3D-CRT) at 18 MV. Materials and methods 68 CIEDs (64 implantable cardioverter-defibrillators (ICDs) and 4 cardiac pacemakers (PMs)) were located on the left chest position on a slab phantom and irradiated under telemetrical surveillance either directly, or distant to 3D-CRT or FFF-VMAT, dose-rate 2500 cGy/min, and target dose of 150 Gy. Devices were placed within, close by (2.5 cm and 5 cm), and distant (35 cm) to the radiation field. Scatter radiation (SR) and photon neutrons (PN) were recorded. CIEDs were investigated in following groups: 1a) 18 MV 3D-CRT − 4 ICDs/4 PMs out of radiation field, 1b) 18 MV open field − 4 ICDs/4 PMs within radiation field, 2) 6 MV FFF-VMAT, 15 ICDs in 35 cm distance to VMAT, 3) 10 MV-FFF VMAT, 15 ICDs in 35 cm distance to VMAT, 4) 6 MV FFF-VMAT, 15 ICDs in 2.5 cm distance to VMAT, 5) 10 MV FFF-VMAT, 15 ICDs in 2.5 cm distance to VMAT. Results No incidents occurred at 6 MV FFF. 10 MV FFF-VMAT and 18 MV 3D-CRT resulted in data loss, reset, and erroneous sensing with inhibition of pacing (leading to inadequate defibrillation) in 8/34 ICDs and 2/4 PMs which were not located within radiation. Direct radiation triggered instantaneous defibrillation in 3/4 ICDs. Conclusions 6 MV FFF-VMAT is safe even at high dose-rates of 2500 cGy/min, regardless whether CIEDs are located close (2.5 cm) or distant (35 cm) to the radiation beam. CIEDs should never be placed within radiation and energy should always be limited to 6 MV. At 6 MV, VMAT at high dose-rates can be used to treat tumors, which are located close to CIEDs.

Purpose Immune checkpoint inhibitors have shown efficacy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) gastrointestinal (GI) cancers. However, depth and duration of clinical response is not uniform. We assessed tumor mutation burden (TMB) as a response marker in patients with GI cancers treated with immune checkpoint inhibitors. Methods Detailed clinical and response data were collected from six patients with metastatic MSI-H/dMMR GI cancers treated with immune checkpoint inhibitors. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumors and matched normal tissue were profiled by targeted next generation sequencing (127 gene panel, size 0.8 Mb). Impact of included mutation types, germline filtering methodology and different variant allele frequency thresholds on TMB estimation was assessed. Results Objective radiographic responses were observed in all six patients, and complete response was achieved in two of the six patients. Responses were durable (minimum 25 months). TMB estimates were clearly above the two recently reported cut-offs for metastatic colorectal cancer of 12 or 37 mutations per megabase for five of six patients, respectively, while one patient had borderline TMB elevation. TMB did not show an association with extent and duration of response but was influenced by included mutation types, germline filtering method and variant allele frequency threshold. Conclusion Our case series confirms the clinical benefit of immune checkpoint blockade in patients with metastatic MSI-H/dMMR GI cancers and illustrates the vulnerability of TMB as predictive marker in a subset of patients.

In 2018, the American Board of Anesthesiology (ABA) became the first US medical specialty certifying board to incorporate an Objective Structured Clinical Examination (OSCE) into its initial certification examination system. Previously, the ABA's staged examination system consisted of 2 written examinations (the BASIC and ADVANCED examinations) and the Standardized Oral Examination (SOE). The OSCE and the existing SOE are now 2 separate components of the APPLIED Examination. This report presents the results of the first-year OSCE administration. A total of 1410 candidates took both the OSCE and the SOE in 2018. Candidate performance approximated a normal distribution for both the OSCE and the SOE, and was not associated with the timing of the examination, including day of the week, morning versus afternoon session, and order of the OSCE and the SOE. Practice-based Learning and Improvement was the most difficult station, while Application of Ultrasonography was the least difficult. The correlation coefficient between SOE and OSCE scores was 0.35 ([95% confidence interval {CI}, 0.30-0.39]; P < .001). Scores for the written ADVANCED Examination were modestly correlated with scores for the SOE (r = 0.29 [95% CI, 0.25-0.34]; P < .001) and the OSCE (r = 0.15 [95% CI, 0.10-0.20]; P < .001). Most of the candidates who failed the SOE passed the OSCE, and most of the candidates who failed the OSCE passed the SOE. Of the 1410 candidates, 77 (5.5%) failed the OSCE, 155 (11.0%) failed the SOE, and 25 (1.8%) failed both. Thus, 207 (14.7%) failed at least 1 component of the APPLIED Examination. Adding an OSCE to a board certification examination system is feasible. Preliminary evidence indicates that the OSCE measures aspects of candidate abilities distinct from those measured by other examinations used for initial board certification.

Significance Vision screenings are conducted to detect significant refractive errors, amblyopia, and ocular diseases. Vision screening devices are desired to have high testability, sensitivity, and specificity. Spot has demonstrated high testability, but previous reports suggest that the Spot has low sensitivity for detecting amblyogenic hyperopia and moderate sensitivity for amblyogenic astigmatism. Purpose This study assessed the concurrent validity of detecting amblyogenic refractive errors by the Spot (v.1.1.50; Welch Allyn Inc., Skaneateles Falls, NY) compared with cycloplegic retinoscopy. Methods A total of 475 subjects (24 to 96 months) were screened by Spot and then received a masked comprehensive examination. Sensitivity and specificity, Bland-Altman plot, receiver operating characteristic area under the curve, and paired t test were evaluated by comparing the results of the Spot (v1.1.50) using the manufacturer referral criteria with the results of the comprehensive examination using the 2013 American Association for Pediatric Ophthalmology and Strabismus criteria. Results The Spot (v.1.1.50) referred 107 subjects (22.53%) for the following: 18.73% (89/475) astigmatism, 4.63% (22/475) myopia, 0.42% (2/475) hyperopia, and 2.11% (10/475) anisometropia. The sensitivity and specificity of the Spot vision screener for detecting amblyogenic risk factors were 86.08% (95% confidence interval [CI], 76.45 to 92.84%) and 90.15% (95% CI, 86.78 to 92.90%). Areas under the curve were 0.906 (95% CI, 0.836 to 0.976) for hyperopia, 0.887 (95% CI, 0.803 to 0.972) for spherical equivalent, and 0.914 (95% CI, 0.866 to 0.962) for astigmatism. A modified hyperopia criteria cutoff of greater than +1.06 D improved the sensitivity from 25 to 80% with 90% specificity. The current cutoff criterion, greater than -1.75 D, for astigmatism seemed optimal. Conclusions This study shows that the Spot vision screener accurately detects low spherical refractive errors and astigmatism. Lowering the hyperopia cutoff criteria from the current Spot screener referral criteria improves the sensitivity with desired (high) specificity.

ObjectiveTGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.DesignAs we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.ResultsTgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.ConclusionsTaken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.

形態: カラー図版あり, Physical characteristics: Original contains color illustrations, Accepted: 2020-01-16, 資料番号: PA2010056000

International audience; Calibration, the estimation of model parameters based on fitting the model to experimental data, is among the first steps in many applications of process-based models and has an important impact on simulated values. We propose a novel method of developing guidelines for calibration of process-based models, based on development of recommendations for calibration of the phenology component of crop models. The approach was based on a multi-model study, where all teams were provided with the same data and asked to return simulations for the same conditions. All teams were asked to document in detail their calibration approach, including choices with respect to criteria for best parameters, choice of parameters to estimate and software. Based on an analysis of the advantages and disadvantages of the various choices, we propose calibration recommendations that cover a comprehensive list of decisions and that are based on actual practices.

Liver fibrosis is characterized by the accumulation of extracellular matrix (ECM) resulting in the formation of fibrous scars. In the clinic, liver biopsies are the standard diagnostic method despite the potential for clinical complications. miRNAs are single-stranded, non-coding RNAs that can be detected in tissues, body fluids and cultured cells. The regulation of many miRNAs has been linked to tissue damage, including liver fibrosis in patients, resulting in aberrant miRNA expression/release. Experimental evidence also suggests that miRNAs are regulated in a similar manner in vitro and could thus serve as translational in vitro–in vivo biomarkers. In this work, we set out to identify and characterize biomarkers for liver fibrosis that could be used in vitro and clinically for research and diagnostic purposes. We focused on miRNAs released from hepatic 3D cultures exposed to methotrexate (MTX), which causes fibrosis, and acetaminophen (APAP), an acute hepatotoxicant with no clinically relevant association to liver fibrosis. Using a 3D in vitro model, we corroborated compound-specific responses as we show MTX induced a fibrotic response, and APAP did not. Performing miRNA-seq of cell culture supernatants, we identified potential miRNA biomarkers (miR-199a-5p, miR-214-3p, niRNA-125a-5p and miR-99b-5p) that were associated with a fibrotic phenotype and not with hepatocellular damage alone. Moreover, transfection of HSC with miR-199a-5p led to decreased expression of caveolin-1 and increased α-SMA expression, suggesting its role in HSC activation. In conclusion, we propose that extracellular miR-214-3p, miR-99b-5p, miR-125a-5p and specifically miR-199a-5p could contribute towards a panel of miRNAs for identifying liver fibrosis and that miR-199a-5p, miR-214-3p and miR-99b-5p are promoters of HSC activation.

Purpose: Patients with inflammatory bowel diseases, that is, ulcerative colitis and Crohn's disease (CD), face an increased risk of developing colorectal cancer (CRC). Evidence, mainly from ulcerative colitis, suggests that TP53 mutations represent an initial step in the progression from inflamed colonic epithelium to CRC. However, the pathways involved in the evolution of CRC in patients with CD are poorly characterized. Experimental Design: Here, we analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions, by targeted next-generation sequencing of 563 cancer-related genes and array-based comparative genomic hybridization. The results were compared with 24 sporadic CRCs with similar histomorphology (i.e., mucinous adenocarcinomas), and to The Cancer Genome Atlas data (TCGA). Results: CD-CRCs showed somatic copy-number alterations (SCNAs) similar to sporadic CRCs with one notable exception: the gain of 5p was significantly more prevalent in CD-CRCs. CD-CRCs had a distinct mutation signature: TP53 (76% in CD-CRCs vs. 33% in sporadic mucinous CRCs), KRAS (24% vs. 50%), APC (17% vs. 75%), and SMAD3 (3% vs. 29%). TP53 mutations and SCNAs were early and frequent events in CD progression, while APC, KRAS, and SMAD2/4 mutations occurred later. In four patients with CD-CRC, at least one mutation and/or SCNAs were already present in non-dysplastic colonic mucosa, indicating occult tumor evolution. Conclusions: Molecular profiling of CD-CRCs and precursor lesions revealed an inflammation-associated landscape of genome alterations: 5p gains and TP53 mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predicting disease progression and distinguishes CD-associated from sporadic colorectal neoplasia. Clin Cancer Res; 24(20); 4997–5011. ©2018 AACR.

Thymomas are the most frequent adult mediastinal cancers. Their etiology is unknown and their pathogenesis poorly understood. Racial, ethnic and environmental factors influence tumorigenesis in many cancers, but their role in thymomas remains unclear to date. In this study that included pretreatment thymoma cases from India and Germany (n = 37 and n = 77, respectively) we compared i) the prevalence of the thymoma-specific chromosome 7 c.74146970T > A mutation of the GTF2I gene in type A and AB thymomas; ii) epidemiological features; and iii) the frequency of myasthenia gravis (MG). Due to a known predominance of GTF2I mutation in A and AB histotypes, we included only a marginal number of type B thymomas as a control group in both cohorts. While the distribution of histological types between the cohorts was similar (p = 0.1622), Indian patients were strikingly younger (p < 0.0001; median age 50 vs. 65 years) and showed significantly lower tumour stage (Masaoka-Koga stage I) at primary diagnosis (p = 0.0005) than the German patients. In patients with known MG status (n = 17 in Indian and n = 25 in German cohort), a clear trend towards more frequent MG was observed in the Indian group (p = 0.0504; 48 vs. 82%). The prevalence of the GTF2I mutation (analysed in n = 34 Indian and n = 77 German patients) was identical in the two cohorts. We conclude that racial-ethnic and environmental factors do not significantly influence the most common molecular feature of thymomas but may have an impact on the timing of clinical presentation.

In the framework of the German Interdisciplinary Sarcoma Group GISG-04/NOPASS trial, we evaluated soft tissue sarcoma samples taken before and after neoadjuvant pazopanib therapy using histopathology and next generation sequencing (NGS) to find potential predictive biomarkers. We also aimed to improve the genetically based sarcoma classification and to elucidate additional potentially druggable mutations. In total, 30 tumor samples from 18 patients consisting of 12 pre-therapeutic biopsies and 18 resection specimens following neoadjuvant pazopanib therapy were available for analyses. NGS was performed with the Oncomine Focus Assay (Ion Torrent) covering 0.03 Mb of DNA and enabled the detection of genetic variants in 52 cancer-relevant genes. Pathological analysis showed significant regression (≥50%) after pazopanib treatment in only one undifferentiated (pleomorphic) sarcoma. NGS analyses revealed a very high frequency of CDK4 amplification (88%, 7/8) in the group of dedifferentiated liposarcoma. In addition, two potentially druggable mutations, a MAP2K1 missense mutation (E203K) and a BRAF missense mutation (V600E), were traceable in two undifferentiated (pleomorphic) sarcoma patients (11%, 2/18). Our findings demonstrate that NGS testing is a powerful technology helping to improve diagnostic accuracy and offering some patients the chance for personalized medicine even in a “mutation unlikely” cohort like STS.

OBJECTIVE: To examine the size and distribution of the advanced practice psychiatric nurse workforce relative to the total psychiatry workforce to determine whether nurses are predominantly working in areas with higher or lower levels of behavioral health specialists. METHODS: State-level data for psychiatric nurses were obtained from the American Nurses Credentialing Center, and included mental health psychiatric nurse practitioners, adult psychiatric nurse practitioners, child psychiatric clinical nurse specialists, and adult psychiatric clinical nurse specialists. Supply estimates of the full psychiatry workforce were calculated for comparison purposes. State population estimates were obtained from U.S. Census Bureau data. State workforce estimates were converted to a 1:100,000 provider-to-population ratio to analyze the density of providers across states. RESULTS: In 2018, the psychiatric workforce supply was estimated to be composed of 66,740 providers, including psychiatrists ( n = 47,046; 71%), psychiatric nurses ( n = 17,534; 26%), physician assistants ( n = 1,164; 2%), and psychiatric pharmacists ( n = 966; 1%). Overall, psychiatric providers appeared to be most densely concentrated in the northeast region of the United States. A dearth of providers was most pronounced within areas in the 12-state Midwest region, southern states, California, and Nevada. The average concentration of psychiatric workers was 22.61 per 100,000 population. CONCLUSIONS: The findings of this study find inconsistent pattern of how psychiatric nurses are distributed relative to the rest of the workforce, but reinforce the idea that they are essential in addressing care needs in areas with low concentrations of psychiatry specialists—especially if they are authorized to work to the full extent of their training/education.

Purpose The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. Methods [11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19–80 years; BMI range 17.6–36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. Results There were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. Conclusion These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies. Electronic supplementary material The online version of this article (10.1007/s00259-019-04403-7) contains supplementary material, which is available to authorized users.

Modern global agriculture depends heavily on irrigation water to maintain crop productivity. The widely used crop evapotranspiration estimation approach (i.e. FAO-56) can be applied to estimate the irrigation water demand of crops under optimal growth conditions by multiplying the reference evapotranspiration with often empirically determined crop-specific crop coefficients (Kc). To improve the transferability of the Kc approach while keeping the Kc concept as a relatively simple and visual tool for irrigation scheduling, a simulation-based approach to estimate site-specific continuous Kc curves was developed. The presented modeling framework consists of the process-based soil–crop–atmosphere system simulation model DAISY calibrated and validated against an extensive field data set and stochastic weather data to consider climate variability. The simulation-based Kc curves were exemplary estimated for common bean (two sowing dates) and white cabbage for several soils at an experimental site in Eastern Germany. The Kc curve ensembles (each 300 growth periods) generated by the modeling framework provided information on the probability of the Kc curves caused by the site-specific climate variability under recent climate conditions. By changing factors while fixing others (soil characteristics, sowing date), the influence of these factors on the Kc curves and the irrigation water requirement were evaluated. We found that the influence of the factors varied between the crops. The two tested common bean sowing dates had an influence on the Kc curves mainly due to varying growth rates and growth durations. The presented Kc curves may support farmers to make accurate in-season but also long-term estimations of the daily irrigation water demand under local conditions. The probability distribution of the curves provides additional information on the variability of the irrigation water demand due to climate variability.

Acne-like skin reactions frequently occur in patients undergoing treatment with drugs inhibiting the epidermal growth factor receptor. Recently, the effects of vitamin K1 containing cream (Reconval K1) as prophylactic skin treatment in addition to doxycycline were explored in a double-blind randomized phase II trial (EVITA) in patients with metastatic colorectal cancer receiving cetuximab. EVITA demonstrated a trend towards less severe skin rash in Reconval K1-treated patients using the tripartite WoMo skin reaction grading score as a thorough tool for quantification of drug related skin reactions. This gender-specific analysis of the EVITA trial evaluated the application of the WoMo score for assessment of epidermal growth factor receptor (EGFR)-related skin toxicities according to treatment arm and gender. To show the robustness of results parametric and non-parametric statistical analyses were conducted. All three parts of the WoMo score independently demonstrated the superiority of the treatment arm (Reconval K1) regarding a significant reduction in acneiform skin reactions in women. Men did not benefit from Reconval K1 cream at any time point in none of the WoMo score analyses. The treatment effect in women was confirmed by the use of skin rash categories based on the final WoMo overall score and mixed effect longitudinal multiple linear regression analysis. The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne-like skin rash. Part C of the WoMo score seems to be sufficient for quantification of drug related skin toxicities in further studies. Standard WoMo skin reaction score values for future studies are provided., publishedVersion

Integrated soil fertility management options are being promoted as ways of adapting agricultural systems to sustain yields on highly degraded and poor soils encountered throughout West Africa. The efficiency of these practices may be affected by high variability and uncertainty associated with seasonal rainfall, especially for areas such as Cote d’Ivoire, where intra-seasonal rainfall has been observed to change from 1 year to another. The DSSAT crop simulation model was used in this study as a tool to evaluate the impacts of soil improvement options including inorganic fertilizer and conservation agriculture generating higher carbon sequestration and crop yield in maize agro-ecosystems. The model was calibrated using agronomic data for three cropping seasons from 2009 to 2010 in Goulikao (Center-West Cote d’Ivoire) and Aheremou 2 (Central Cote d’Ivoire), respectively and validated against independent datasets of yield of 2003–2004 seasons in the buffer zone of the Lamto Natural Reserve, Central Cote d’Ivoire. The model predicted average maize yields of 1454 kg ha−1 across the sites versus an observed average value of 1736 kg ha−1, R2 of 0.72, and RMSE of 597 kg ha−1 after the default values for stable soil organic matter fraction used in the model were substituted by the estimated one. For the validation, the predicted higher maize yield was consistently related to fallow biomass inputs and different rates of fertilizer, thus generating a RMSE of total aboveground biomass and grain yield of 606 kg ha−1 and 350 kg ha−1, respectively. The impact of fallow residues and cropping sequence on subsequent maize yield was simulated and compared with conventional fertilizer and control data using 12 years historic climate time series. We conclude that soil fertility improvements through conservation agriculture can sustain grain yield at the same level as conventional inputs of urea against larger climate variability. However, this system may be substituted by conventional agriculture when climate forecast reveals a dry cropping season year.

Background Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours. Methods In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644. Findings Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [ Interpretation In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX. Funding The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.

This prospective trial aimed to investigate whether tumor-specific cKIT and PDGFRA mutations can be detected and quantified in circulating tumor (ct)DNA in patients with active GIST, and whether detection indicates disease activity. We included 25 patients with active disease and cKIT or PDGFRA mutations detected in tissue. Mutant ctDNA was detected in the peripheral blood plasma using allele-specific ligation (L-)PCR and droplet digital (d)PCR. CtDNA harboring tumor-specific cKIT or PDGFRA mutations was detected at least once in 16 out of 25 patients using L-PCR (64%) and in 20 out of 25 patients with dPCR (80%). Using dPCR, the absolute numbers of ctDNA fragments (DNA copies/ml) and the mutant allele frequency (MAF; in percent of wild-type control) strongly correlated with tumor size expressed as RECIST1.1 sum of diameter (SOD) in mm (ρ = 0.3719 and 0.408, respectively, p < 0.0001) and response status (ρ = 0.3939 and 0.392, respectively, p < 0.0001 and p < 0.001). Specificity of dPCR for detection of progression was 79.2% with a sensitivity of 55.2% and dPCR discriminated CR from active disease with a specificity of 96% and s sensitivity of 44.7%. With L-PCR, correlations of MAF with tumor size and response status were less prominent. Serial ctDNA measurement reflected individual disease courses over time. Targeted panel sequencing of four patients detected additional driver mutations in all cases and secondary resistance mutations in two cases. Thus, ctDNA indicates disease activity in patients with GIST and should be incorporated as companion biomarker in future prospective trials.

ObjectivesIntraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can progress to invasive pancreatic cancer. Associations between oncogenesis and oral microbiome alterations have been reported. This study aims to investigate a potential intracystic pancreatic microbiome in a pancreatic cystic neoplasm (PCN) surgery patient cohort.DesignPaired cyst fluid and plasma were collected at pancreatic surgery from patients with suspected PCN (n=105). Quantitative and qualitative assessment of bacterial DNA by qPCR, PacBio sequencing (n=35), and interleukin (IL)-1β quantification was performed. The data were correlated to diagnosis, lesion severity and clinical and laboratory profile, including proton-pump inhibitor (PPI) usage and history of invasive endoscopy procedures.ResultsIntracystic bacterial 16S DNA copy number and IL-1β protein quantity were significantly higher in IPMN with high-grade dysplasia and IPMN with cancer compared with non-IPMN PCNs. Despite high interpersonal variation of intracystic microbiota composition, bacterial network and linear discriminant analysis effect size analyses demonstrated co-occurrence and enrichment of oral bacterial taxa including Fusobacterium nucleatum and Granulicatella adiacens in cyst fluid from IPMN with high-grade dysplasia. The elevated intracystic bacterial DNA is associated with, but not limited to, prior exposure to invasive endoscopic procedures, and is independent from use of PPI and antibiotics.ConclusionsCollectively, these findings warrant further investigation into the role of oral bacteria in cystic precursors to pancreatic cancer and have added values on the aetiopathology as well as the management of pancreatic cysts.

Preoperative devascularization might improve local control and thus the outcome of patients with soft tissue sarcoma (STS). The multikinase inhibitor pazopanib has antiangiogenic effects and is approved for treating metastatic STS. We conducted a trial of preoperative pazopanib therapy in high-risk STS. This single-arm, phase II trial included patients with resectable, non-metastatic, treatment-naive, high-risk STS. Patients received pazopanib 800 mg daily while waiting for surgery (21-day ‘window of opportunity’). The primary endpoint was metabolic response rate (MRR; proportion of patients with ≥ 50% reduction of mean standardized uptake value [SUVmean] in post- vs. pretreatment fluorodeoxyglucose–positron emission tomography/computed tomography [FDG-PET-CT]). Planned sample size was 35 patients (type I error, 5%; type II error, 20%). A translational substudy explored associations between response and concentration of circulating angiogenic factors. Futility analysis was performed after 21 patients (11 female, mean age 67 years; liposarcoma n = 15); 17/21 patients were evaluable for the primary endpoint. The MRR was 1/17 (5.9%, 95% confidence interval

Background: Changes in transcranial magnetic stimulation motor map parameters can be used to quantify plasticity in the human motor cortex. The golden standard uses a counting analysis of motor evoked potentials (MEPs) acquired with a predefined grid. Recently, digital reconstruction methods have been proposed, allowing MEPs to be acquired with a faster pseudorandom procedure. However, the reliability of these reconstruction methods has never been compared to the golden standard.Objective: To compare the absolute reliability of the reconstruction methods with the golden standard.Methods: In 21 healthy subjects, both grid and pseudorandom acquisition were performed twice on the first day and once on the second day. The standard error of measurement was calculated for the counting analysis and the digital reconstructions.Results: The standard error of measurement was at least equal using digital reconstructions.Conclusion: Pseudorandom acquisition and digital reconstruction can be used in intervention studies without sacrificing reliability. (C) 2018 The Authors. Published by Elsevier Inc.

This study analyses forest reference level in terms of loss, gain and transitions among forest, cocoa agroforestry, cassava, maize, settlement and others in the Kloto district (Togo) for REDD+ and sustainable forest and agriculture. The pixel-based classification was adopted and combined with the extended change matrix quantity and intensity analysis using 32-year (1985–2017) Landsat data and land use information from land owners and farmers. Results indicate an active forest loss (19.5%) with dormant gain (0.8%). Forest is involved in most transitions as the most targeted category with the largest transition being a forest to cocoa agroforestry while the avoiding transition was from forest, cocoa agroforestry, maize, cassava and settlement to unclassified classes (e.g. road, water body) and vice versa. Other targeting categories were from forest to settlement, cassava and maize Thus, both cash and food crops are major contributors of forest loss. The study concludes that cropland land degradation is the main reason that explains the significant conversion of forest lands to stable agricultural lands. Therefore, review of the existing cropping and farming systems by promoting agroecology systems (e.g. agroforestry, rotational cropping, mixing cropping with pulses) to sustain and restore soil degradation while mitigating climate change, forest degradation and provide food security for the rural communities is recommended. Economic measures such as: trade-off compensations for agroecology practices and afforestation and reforestation through farmer’s association initiatives could be encouraged to limit forest extensions.

Introduction: Due to the COVID-19 pandemic and prompted by recent federal and state policy shifts impacting behavioral health care delivery, the use of telebehavioral health has rapidly increased. This qualitative study describes behavioral health provider perspectives on the use of telebehavioral health before and during the pandemic and how policy changes impacted access to and utilization of behavioral health services in Michigan. Materials and Methods: A convenience sample of 31 licensed and nonlicensed behavioral health providers operating in Michigan participated in semi-structured interviews between July and August 2020. Interviews were audio-recorded, transcribed, and analyzed by using inductive methods. Results: The thematic analysis resulted in four overarching themes: (1) increased access to care; (2) maintenance of quality of care; (3) minimal privacy concerns; and (4) client and provider satisfaction. Discussion: During and post-pandemic, providers need flexibility to determine whether in-person or telebehavioral health services, including audio-only, best meet client needs. Providers identified several populations for which telebehavioral health was less accessible: clients with serious mental illness and substance use disorder, those with no broadband Internet access, children, and older adults. Additional training in telebehavioral health service provision can positively impact quality of care. Conclusion: Policies that support reimbursement parity and expand provider use of telebehavioral health services should be maintained after the COVID-19 pandemic ends to avoid imposing barriers to accessing behavioral health care barriers post-pandemic.

Research Objective To understand the impact of state and federal policy changes during the COVID‐19 pandemic on use and effectiveness of telebehavioral health based on provider experience, Study Design Between July and August 2020, researchers conducted one‐hour interviews with 31 Michigan‐based behavioral health providers from 15 counties. These semi‐structured interviews included the following topics: (1) Experience with telebehavioral health prior to, and during, the pandemic, (2) Changes in cost of, access to, and quality of care between in‐person and telebehavioral health services, and (3) Telebehavioral health's impact on providers and clients. The interviews were recorded, transcribed, and later analyzed with Dedoose™ software to identify common themes between responses. Population Studied Interviewees included a psychiatrist, psychologists, registered nurses, clinical social workers, mental health counselors, substance use disorder counselors, applied behavior analysts, and peer support specialists. Principal Findings Telebehavioral health provision increased during the pandemic, with all interviewees reporting providing telebehavioral health services ‐ 19 for the first time. All interviewees agreed that newly‐enacted state and federal policies made it legally and financially viable to continue safely providing services during the pandemic. Fourteen interviewees reported increased job satisfaction and decreased feelings of burnout. No interviewees reported a breach of health data as a result of using non‐public facing audio‐visual communications. Overall, interviewees agreed telebehavioral health services were at least as effective as in‐person services. Clients with certain conditions (social anxiety, post‐traumatic stress disorder) seemed to respond better to telebehavioral health services. Clients with other conditions (substance use disorder, developmental disabilities) responded less favorably. Thirty interviewees reported clients were satisfied with telebehavioral health services, with some clients preferring them over in‐person services. Twenty‐eight reported telebehavioral health reduced or removed barriers that would have otherwise prevented these clients from receiving care, such as the need to arrange for transportation, childcare, or time off from work. This resulted in decreased no‐show rates and more regular contact between providers and clients. Access to care for geographically isolated populations increased when audio‐only telebehavioral health was authorized; these populations used to have to travel further for care, and often lacked high‐speed internet and internet‐connected devices necessary for audio‐visual telehealth services. Conclusions Despite telebehavioral health's effectiveness and widespread client approval, interviewees expressed that their current work with telehealth was only possible because of recent policy changes. Should those policies revert back, providers may not be able to continue to provide these services. For some clients, such as those who are geographically isolated and unable to engage with anything but audio‐only telehealth, reverting these policies would mean notable barriers and/or losing access to care entirely. Implications for Policy or Practice In Michigan, policy implications for both private and public insurances include continuing audio‐only telehealth authorization and improving coverage of telebehavioral health by instituting service and reimbursement parity policies. Such policies could be enacted through Medicaid plan amendments or amendments to Michigan's Insurance Code. For federal policymakers, implications include amending HIPAA to improve acceptability of non‐public facing audio‐visual communications and extending certain provisions of the CARES Act, such as allowing audio‐only telehealth as a modality of last resort, through new laws and regulations. Primary Funding Source Institute for Healthcare Policy and Innovation.

Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32&ndash, 80, lesion diameter 7.0 cm, 1&ndash, 14.5, median, range), five (14%) showed associated lymphomas, including four (11%) thymic MALT lymphomas and one (3%) diffuse large B-cell lymphoma. One additional case showed a clonal B-cell-receptor rearrangement without evidence of lymphoma. Twelve (33%) patients (7 women) suffered from partially overlapping autoimmune diseases: systemic lupus erythematosus (n = 4, 11%), rheumatoid arthritis (n = 3, 8%), myasthenia gravis (n = 2, 6%), asthma (n = 2, 6%), scleroderma, Sj&ouml, gren syndrome, pure red cell aplasia, Grave&rsquo, s disease and anti-IgLON5 syndrome (each n = 1, 3%). Among 11 primary thymic MALT lymphomas, remnants of LESA-like TH were found in two cases (18%). In summary, LESA-like TH shows a striking association with autoimmunity and predisposes to lymphomas. Thus, a hematologic and rheumatologic workup should become standard in patients diagnosed with LESA-like TH. Radiologists and clinicians should be aware of LESA-like TH as a differential diagnosis for mediastinal mass lesions in patients with autoimmune diseases.

BACKGROUND Millions of Americans are injured each year, with 75% suffering orthopedic injuries. Those with orthopedic injury often experience postinjury symptoms, such as anxiety, that negatively influence long-term outcomes. The purpose of this systematic review was to evaluate (1) the prevalence of anxiety symptoms chronologically in relation to time of orthopedic injury, (2) the associations of anxiety symptoms with other symptoms in individuals with orthopedic injury, and (3) the associations between anxiety symptoms and functional performance and mental health outcomes in individuals with orthopedic injury. METHODS The databases CINAHL, Ovid MEDLINE, Ovid PsycInfo, Ovid Embase, ProQuest, and ClinicalTrials.gov were searched on June 25, 2020. Studies were selected for review if (1) participants were 16 years or older, (2) the prevalence of anxiety symptoms was listed, (3) anxiety symptoms were assessed using a validated instrument, (4) the study was published in English, and (5) more than 50% of the participants suffered orthopedic injury to the appendicular skeleton or pelvic ring. RESULTS Anxiety symptoms were present in 11.5%-55.9% of individuals up to 10 years after orthopedic injury and often co-occurred with those of depression, pain, and posttraumatic stress disorder to negatively influence functional performance and mental health outcomes. CONCLUSIONS Anxiety symptoms post-orthopedic injury are highly prevalent and persistent. Anxiety symptoms are associated with other distressing symptoms and influence long-term outcomes. These findings highlight the need to screen for and treat anxiety symptoms following orthopedic injury and may help in designing future self-management interventions.

Coronavirus 2 (SARS-CoV-2) infection and the resulting COVID-19 illness vary from asymptomatic disease, mild upper respiratory tract infection, pneumonia1, to a life-threatening multi-organ failure with case fatality rates ranging from 0.27–13.4%2,3. Despite increasing knowledge of the clinical and immunological features underlying COVID-191,4−6, biological variables explaining the course of infection and its severity remain elusive. At the entry site of SARS-CoV2, the oropharyngeal microbiome represents a hub integrating viral and immune signals at the start of the infection7–10. To evaluate the role of the oropharyngeal microbiome in COVID-19, we performed a multi-center, cross-sectional clinical study analyzing the oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate and severe COVID-19 encompassing a total of 345 participants. Significantly reduced microbiome diversity and high dysbiosis were observed in hospitalized patients with severe COVID-19, which was further associated with a loss of microbial genes and metabolic pathways. In this cohort, diversity measures were also associated with need for intensive care treatments as major clinical parameters in COVID-19. We further applied random forest machine learning to unravel microbial features for segregating clinical outcomes in hospitalized cases, and observed oropharyngeal microbiome abundances of Haemophilus or Streptococcus species as most important features. These findings provide insights into the role of the oropharyngeal microbiome in SARS-CoV-2 infection, and may suggest new biomarkers for COVID-19 severity.

As any procedure in medicine, the transfusion of blood products to the patient involves benefits and risks. The benefits of increased oxygen carrying capacity with the ability to deliver oxygen to the tissue is clear in the setting of severe hemorrhage. The risks are not as clear. While patients are mainly concerned with infectious risks, there are other risks that must be considered by the provider.

Only a small subset of colorectal cancer (CRC) patients benefits from immunotherapies, comprising blocking antibodies (Abs) against checkpoint receptor “programmed-cell-death-1” (PD1) and its ligand (PD-L1), because most cases lack the required mutational burden and neo-antigen load caused by microsatellite instability (MSI) and/or an inflamed, immune cell-infiltrated PD-L1+ tumor microenvironment. Peroxisome proliferator-activated-receptor-gamma (PPARγ), a metabolic transcription factor stimulated by anti-diabetic drugs, has been previously implicated in pre/clinical responses to immunotherapy. We therefore raised the hypothesis that PPARγ induces PD-L1 on microsatellite stable (MSS) tumor cells to enhance Ab-target engagement and responsiveness to PD-L1 blockage. We found that PPARγ-agonists upregulate PD-L1 mRNA/protein expression in human gastrointestinal cancer cell lines and MSS+ patient-derived tumor organoids (PDOs). Mechanistically, PPARγ bound to and activated DNA-motifs similar to cognate PPARγ-responsive-elements (PPREs) in the proximal −2 kb promoter of the human PD-L1 gene. PPARγ-agonist reduced proliferation and viability of tumor cells in co-cultures with PD-L1 blocking Ab and lymphokine-activated killer cells (LAK) derived from the peripheral blood of CRC patients or healthy donors. Thus, metabolic modifiers improved the antitumoral response of immune checkpoint Ab, proposing novel therapeutic strategies for CRC.

Once considered futuristic, machine learning is already integrated into our everyday life and will shape many areas of our daily life in the future: This success is mainly due to the progress in machine learning and the increase in computing power. While machine learning is used to solve partial problems in autonomous driving, the support of high-resolution maps severely limits the use of autonomous vehicles in unknown areas. At the same time, the structuring of the overall problem into modular subsystems for perception, self-localization, planning, and control limits the performance of the systems. A particularly promising alternative is end-to-end learning, which optimizes the system as a whole. In this work, we investigate the application of an end-to-end learning method for autonomous driving, employing reinforcement learning. For this purpose, a system is developed which allows the examination of different reinforcement learning approaches in a simulated environment. The system receives simulated images of the front camera as input and provides the control values for steering angle, accelerator, and brake pedal position as direct output. The desired behavior is learned automatically through interaction with the environment. The reward function is currently optimized for following a lane at the highest possible speed. Using specially modeled environments with different levels of detail, multiple deep reinforcement learning approaches are compared. Among other aspects, the extent to which a transferability of trained models to unknown environments is possible is examined. Our investigations show that Soft Actor-Critic is the best choice of the tested algorithms concerning learning speed and the ability to generalize to unseen environments.

Background High response rates (RR) have led to the approval of the CD19 specific CAR T-cell products Axicabtagene-Ciloleucel and Tisagenlecleucel for the treatment of refractory/relapsed B-cell precursor ALL (BCP-ALL) and Diffuse Large B-cell lymphoma (DLBCL). However, only a subgroup of patients achieves long-term remission. Additionally, most patients experience adverse effects such as cytokine release syndrome or neurotoxicity. Therefore, we need to better understand mechanisms of relapse and disease progression or toxicity to improve effectiveness of CD19 CAR T-cell therapy. As the gut microbiota plays an important role in modulating T-cell based immunotherapy, we hypothesize, that its signature also impacts clinical outcomes of CAR T-cell therapy. Materials and Methods We are currently collecting and 16S rRNA sequencing fecal biospecimen from BCP-ALL and DLBCL patients before, during and after treatment with Axicabtagene-Ciloleucel and Tisagenlecleucel at the University Hospital of the LMU. Microbiota data are integrated into a patient-centered ‘hospitalome’ including onset and type of infection and of immunotoxicity, concomitant anti-infective and immunosuppressive agents as well as response to CAR T-cell therapy. Results Preliminary data analysis revealed, that 4–14 days after CAR T-cell infusion the alpha diversity of the gut microbiome of each patient decreases drastically, whereas pre-lymphodepletion gut microbiota has a high diversity. Furthermore, the microbiota composition during the course of treatment changes as seen by beta diversity changes. In more detail, after CAR T-cell infusion, we observed instances of gut microbiota mono-domination with Enterococci or the genus Rikinella. Conclusions The gut microbiome of patients being treated with CAR T cells undergoes large and diverse compositional changes. We currently explore how this microbiome heterogeneity relates to the distinct responses and immunotoxicity of patients after CAR T-cell therapy. Hence, this study will enable microbiome-based stratification of patients, in order to predict and improve patient outcome to this personalized T-cell recruiting immunotherapy approach. Disclosure Information V. Blumenberg: None. E. Zamir: None. S. Schmidt: None. R. Gaiser: None. N. Cullin: None. V. Bucklein: None. C. Schmidt: None. M. von Bergwelt: None. E. Elinav: None. C.K. Stein-Thoeringer: None. M. Subklewe: None.