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Infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) commonly harbors the classic ETV6-NTRK3 translocation. However, there are recent reports of mesenchymal tumors with IFS-like morphology harboring fusions of other receptor tyrosine kinases or downstream effectors, including NTRK1/2/3, MET, RET, and RAF1 fusions as well as one prior series with BRAF fusions. Discovery of these additional molecular drivers contributes to a more integrated diagnostic approach and presents important targets for therapy. Here we report the clinicopathologic and molecular features of 14 BRAF-altered tumors, of which 5 had BRAF point mutations and 10 harbored one or more BRAF fusions. Of the BRAF fusion-positive tumors, one harbored two BRAF fusions (FOXN3-BRAF, TRIP11-BRAF) and another harbored three unique alternative splice variants of EPB41L2-BRAF. Tumors occurred in ten males and four females, aged from birth to 32 years (median 6 months). Twelve were soft tissue based; two were visceral including one located in the kidney (cCMN). All neoplasms demonstrated ovoid to short spindle cells most frequently arranged haphazardly or in intersecting fascicles, often with collagenized stroma and a chronic inflammatory infiltrate. No specific immunophenotype was observed; expression of CD34, S100, and SMA was variable. To date, this is the largest cohort of BRAF-altered spindle cell neoplasms with IFS-like morphology, including not only seven novel BRAF fusion partners but also the first description of oncogenic BRAF point mutations in these tumors.

Background & Aims Studies of the effects of direct oral anticoagulants (DOACs) in patients with cirrhosis have been limited by their small sample size, inclusion of patients with well-compensated cirrhosis, short follow-up times, inadequate validation of cirrhosis diagnoses, and non-standard definitions of bleeding. We aimed to systematically determine the characteristics, indications, and outcomes of patients with cirrhosis of all severity classes who received DOACs. Methods We performed a retrospective study of 138 patients with confirmed cirrhosis (93 with Child-Turcotte-Pugh scores of B or C) at a single center who started DOAC therapy (58,984 person-days; median, 181 days per patient) from September 2011 through April 2019. We collected data on clinical characteristics, indications for DOAC use, and outcomes. Standardized and validated definitions for bleeding complications were used. Results Twenty-nine patients (21%) stopped therapy due to a diagnosis of or perceived bleeding. The most common bleeding events were non-variceal upper and lower intestinal bleeding. No pretreatment laboratory parameters were associated with bleeding while patients received treatment, including platelet count (P = .50), international normalized ratio (P = .34), creatinine (P = .27), and model for end-stage liver disease score (P = .22). Frequency of bleeding events related to DOAC did not differ significantly among patients of different Child-Turcotte-Pugh classes (P = .81), DOAC indications (P = .60), or DOAC dosages (P = .10). Higher proportions of patients with hepatocellular carcinoma (P = .01) had major bleeding while receiving. Conclusions Patients with decompensated cirrhosis have significant bleeding and rates of discontinuation of DOACs when they take them long term. Pretreatment laboratory parameters, DOAC dose, and Child-Turcotte-Pugh class were not associated with bleeding; hepatocellular carcinoma was associated with major bleeding.

After a period of rapidly declining U.S. COVID-19 incidence during January-March 2021, increases occurred in several jurisdictions (1,2) despite the rapid rollout of a large-scale vaccination program. This increase coincided with the spread of more transmissible variants of SARS-CoV-2, the virus that causes COVID-19, including B.1.1.7 (1,3) and relaxation of COVID-19 prevention strategies such as those for businesses, large-scale gatherings, and educational activities. To provide long-term projections of potential trends in COVID-19 cases, hospitalizations, and deaths, COVID-19 Scenario Modeling Hub teams used a multiple-model approach comprising six models to assess the potential course of COVID-19 in the United States across four scenarios with different vaccination coverage rates and effectiveness estimates and strength and implementation of nonpharmaceutical interventions (NPIs) (public health policies, such as physical distancing and masking) over a 6-month period (April-September 2021) using data available through March 27, 2021 (4). Among the four scenarios, an accelerated decline in NPI adherence (which encapsulates NPI mandates and population behavior) was shown to undermine vaccination-related gains over the subsequent 2-3 months and, in combination with increased transmissibility of new variants, could lead to surges in cases, hospitalizations, and deaths. A sharp decline in cases was projected by July 2021, with a faster decline in the high-vaccination scenarios. High vaccination rates and compliance with public health prevention measures are essential to control the COVID-19 pandemic and to prevent surges in hospitalizations and deaths in the coming months.

Summary A growing body of evidence suggests that diet quality may predict muscle health. This study found that a “Traditional” dietary pattern predicted greater muscle mass, and an anti-inflammatory diet predicted greater muscle mass and better muscle function over 15 years. These findings reinforce the importance of optimising dietary behaviours for healthy ageing. Introduction Research investigating the roles of individual nutrients in muscle health fails to account for the synergistic relationships between foods and nutrients. This study aimed to investigate the predictive value of diet quality and dietary patterns for muscle mass and function in men over a 15-year period. Methods This longitudinal study was conducted in 522 men from the Geelong Osteoporosis Study with complete dietary and muscle mass or muscle function data at both baseline and 15-year follow-up assessments. Dietary exposures were extracted from food frequency questionnaires and included the Australian Recommended Food Score, the Dietary Inflammatory Index (DII®), and three a posteriori dietary patterns: Plant-focused, Western, and Traditional (Anglo-Australian). Outcome variables included dual-energy X-ray absorptiometry–derived skeletal muscle index (SMI) and muscle function measured with the timed up-and-go (TUG) test. Results An anti-inflammatory diet and higher scores on a Traditional dietary pattern both predicted greater SMI ((B: −0.04 (95%CI −0.08, −0.00) kg/m2) and (B: 0.12 (95%CI 0.04, 0.20) kg/m2), respectively), while a pro-inflammatory diet predicted slower TUG (B: 0.11 (95%CI 0.001, 0.21) sec) over the 15-year follow-up period. These associations remained significant following adjustment for confounding variables. There were no associations observed for other dietary exposures. Conclusion A Traditional dietary pattern higher in vegetables, wholegrain cereals, and animal protein was associated with greater skeletal muscle mass, and an anti-inflammatory diet, also rich in vegetables, fruit, and wholegrain cereals, was associated with greater skeletal muscle mass and better muscle function over 15 years. Supplementary Information The online version contains supplementary material available at 10.1007/s00198-021-06012-3.

Mesenchymal tumors driven by NTRK fusions are clinically and morphologically heterogeneous. With an increasing number of clinicopathological entities being associated with NTRK fusions, the diagnostic and predictive value of the identification of NTRK fusions is uncertain. Recently, mesenchymal tumors in the gastrointestinal tract with NTRK fusions were described as gastrointestinal stromal tumors (GIST), but the nosology of such neoplasms remains controversial. We report eight mesenchymal tumors involving the gastrointestinal tract with NTRK1 or NTRK3 rearrangements. The tumors occurred in six children and two adults, five males and three females (age range 2 months–55 years; median 3.5 years), and involved the small intestine (n = 4), stomach (n = 2), rectum (n = 1), and mesentery (n = 1). Clinical outcomes were variable, ranging from relatively indolent (n = 2) to aggressive diseases (n = 2). Morphologically, the tumors were heterogeneous and could be classified in the following three groups: (1) infantile fibrosarcoma involving the gastrointestinal tract (n = 4), enriched for NTRK3 fusions; (2) low-grade CD34-positive, S100 protein-positive spindle-cell tumors, associated with NTRK1 fusions (n = 2); and (3) unclassified high-grade spindle-cell sarcomas, with NTRK1 fusions (n = 2). By immunohistochemistry, the tumors demonstrated diffuse pan-TRK expression, of variable intensity, and lacked a specific line of differentiation. Four cases expressed CD34, which was coexpressed with S100 protein in three cases. Expression of SOX10, KIT, and DOG1 was consistently absent. Molecular genetic testing identified TPM3–NTRK1 (n = 3), TPR–NTRK1, LMNA–NTRK1, and ETV6–NTRK3 (n = 2), and SPECC1L–NTRK3 in-frame gene fusions. We conclude that the evaluation of mesenchymal spindle-cell neoplasms of the gastrointestinal tract without a definitive line of differentiation should include interrogation of NTRK alterations, particularly in pediatric patients. Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements are clinically and morphologically heterogeneous, and few, if any, seem related to GIST.

Pediatric fibroblastic/myofibroblastic tumors are rare but include a wide variety of benign to malignant tumors. Given their uncommon frequency, they may present as a diagnostic dilemma. This article is focused on using clinical and pathologic clues in conjunction with the increasingly relevant and available molecular techniques to classify, predict prognosis, and/or guide treatment in these tumors.

The gut bacterium Akkermansia muciniphila (A. muciniphila), has been linked to body composition and metabolism. However, the role of lifestyle factors and medication use in these relationships has not been considered. This study aimed to assess the relative abundance of A. muciniphila in participants and investigate its association with obesity, with consideration of potential confounding factors.Participants included 158 men of the Geelong Osteoporosis Study with dual-energy X-ray absorptiometry data, 16S rRNA gene bacterial profiling of stool samples, and lifestyle data. The relative abundance of A. muciniphila was estimated from total sequence reads, while obesity status was quantified by fat mass index (FMI, kg/mIn this cohort (66 ± 12 yr, mean ± SD), the most common medications were proton pump inhibitors (PPIs) (28%), and these were associated with both high FMI and decreased abundance of A. muciniphila. Before and after adjustments for PPIs, participants with substantial A. muciniphila (abundance ≥0.1%, n = 94) compared to very low (abundance0.1%, n = 64), had lower FMI (adjusted -1.33 (95%CI -2.30, -0.36) kg/mIn this sample, relative abundance of A. muciniphila was inversely associated with high FMI, independent of PPI use. The relationship between obesity, reflux medication, and the gut microbiome warrants further investigation.

Purpose: A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS). Patients and Methods: We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue. Results: The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity. Conclusions: These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials. See related commentary by Sleijfer and Lolkema, p. 3897

Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellular matrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis – the chronic nature of insult required and the liver’s unique ability to regenerate – give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of a limited number of common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are expected to contribute to ASD risk given the high heritability. Here, we performed a genome-wide association study (GWAS) on 6222 case-pseudocontrol pairs from the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD. We identified one novel GWS locus from the SPARK GWAS and four significant loci, including an additional novel locus from meta-analysis with a previous GWAS. We replicated the previous observation of significant enrichment of ASD heritability within regulatory regions of the developing cortex, indicating that disruption of gene regulation during neurodevelopment is critical for ASD risk. We further employed a massively parallel reporter assay (MPRA) and identified a putative causal variant at the novel locus from SPARK GWAS with strong impacts on gene regulation (rs7001340). Expression quantitative trait loci data demonstrated an association between the risk allele and decreased expression of DDHD2 (DDHD domain containing 2) in both adult and prenatal brains. In conclusion, by integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.

Aims A unique fibrosarcoma-like tumour of the uterine cervix harbouring a rearrangement of a neurotrophic tyrosine kinase receptor (NTRK) gene (NTRK1 or NTRK3) has recently been described in 11 young women, some with recurrence and/or metastasis. The aims of this study were to expand the morphological spectrum of this tumour by reporting three additional cases that showed adenosarcoma-like features not previously described, one of which is the first reported to respond to targeted therapy, and to evaluate 19 conventional uterine adenosarcomas for evidence of NTRK rearrangement. Methods and results Three patients presented with a polyp or mass confined to the cervix. The constellation of polypoid growth, spindle cell morphology, entrapped endocervical glands and intraglandular stromal projections raised diagnostic consideration for adenosarcoma with stromal overgrowth. Deep cervical wall invasion was present in two cases at hysterectomy, and the third was removed by polypectomy. All three stained for S100 and pan-Trk, but were negative for a spectrum of other diagnostic markers. All three harboured NTRK rearrangements (TPM3-NTRK1, TPR-NTRK1, and SPECC1L-NTRK3). One patient developed pleural metastases at 16 months, received the NTRK inhibitor larotrectinib, and is free of disease 15 months later. Two others are alive without disease. None of the uterine adenosarcomas showed any S100 or pan-Trk staining, or rearrangement of NTRK1, NTRK2 or NTRK3 on next-generation sequencing. Conclusions Unusual adenosarcoma-like spindle cell neoplasms of the cervix may represent an NTRK fusion sarcoma, which can be detected by S100 and pan-Trk staining and confirmed by NTRK molecular testing. Conventional uterine adenosarcomas do not harbour NTRK rearrangements.

Aims The classification of paediatric spindle mesenchymal tumours is evolving, and the spectrum of so-called 'infantile fibrosarcoma' has expanded to include tumours with NTRK, BRAF and MET gene fusions. RET-rearranged paediatric spindle cell neoplasms are an emerging group; there is sparse literature on their clinical, pathological and genetic features, and their nosological place in the canon of soft tissue tumours is uncertain. In this study, we report five RET-rearranged paediatric spindle cell tumours with fusion partners MYH10, KIAA1217 and CLIP2. Methods and results The tumours occurred in the pelvic region, paraspinal region, kidney and subcutaneous tissue of hand and abdomen. The patients' ages ranged from 6 months to 13 years (median 1 year). The tumours were composed of monomorphic spindle cells arranged in a fascicular pattern. Lesional cells had minimally atypical ovoid or tapered nuclei and pale cytoplasm with indistinct borders. Necrosis was not identified. Mitoses numbered three to 12 per 10 high-power field. Cases showed inconsistent and variable expression of S100, CD34 and SMA. Clinical behaviour ranged from small lesions potentially cured by simple resection to large lesions exhibiting metastasis, but responsive to kinase inhibitor therapy. Conclusions Our findings help to define RET-rearranged spindle cell tumours. Although it is likely that these tumours comprise part of the morphological and clinical spectrum of infantile fibrosarcoma (IFS), identification of RET gene alteration is important for its unique therapeutic implications.

Purpose of review The present article aims to provide clinicians with an overview of coagulation testing in individuals with liver disease, to discuss available procoagulants and the rationale for their use, and to provide management strategies in a variety of common clinical scenarios. Recent findings Clinicians and researchers are gaining an increased understanding of the shortfalls of assessing bleeding risk using traditional tests of coagulation. The use of global tests of clot formation, including viscoelastic testing and thrombin generation analysis, continues to evolve and guide the management of these patients. Summary Abnormal coagulation testing in individuals with cirrhosis leads to a variety of difficult clinical scenarios that can be challenging for practitioners. With advanced liver disease, changes in the traditional tests of hemostasis such as the international normalized ratio reflect decreased synthesis of procoagulant factors but do not capture concomitant decreases in anticoagulant factors. In this setting, transfusion thresholds targeting platelet and fibrinogen goals may provide an effective strategy to optimize clot formation. Global tests of clot formation provide practical information to clinicians and can help guide decision making, although optimal target levels have not been validated.

INTRODUCTION Patients with liver disease are at risk of venous thromboembolism (VTE); however, little is understood regarding the safety and efficacy of VTE prophylaxis in patients with cirrhosis. We examined the application of a VTE risk assessment model in VTE prophylaxis decision-making in a closed cohort of hospitalized patients with liver disease. METHODS Sequential patients admitted to an inpatient hepatology service at a tertiary care center were evaluated for need for VTE prophylaxis. Risk assessment by IMPROVE was compared with current practice patterns of VTE prophylaxis. Rates of bleeding and clotting events were noted. RESULTS 98 patient encounters were included in our analysis. 76% of patients received VTE prophylaxis in practice. IMPROVE recommended use of VTE prophylaxis in 19% of patients. Patients who received VTE prophylaxis that was not warranted had significantly lower risk of clotting compared with patients in whom VTE prophylaxis was warranted per IMPROVE. CONCLUSIONS Application of IMPROVE risk assessment would significantly reduce VTE prophylaxis use among hospitalized patients with liver disease. Our findings challenge the "one-size-fits-all" current practice pattern of VTE prophylaxis. Future studies are needed in large cohorts of hospitalized patients with liver disease that include clinical outcomes of bleeding and clotting risk.

Background Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited. Methods A multicenter, retrospective case series investigation of consecutive BRAF‐mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates (according to the modified Response Evaluation Criteria in Solid Tumors, version 1.1); the clinical benefit rate; the time to response; the duration of response; and safety. Results A total of 24 patients with stage IV BRAF‐mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases. Conclusions Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF‐mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing., All clinical trials to date with encorafenib and binimetinib (US Food and Drug Administration–approved in June 2018 for BRAF‐mutated metastatic melanoma) have excluded untreated melanoma brain metastases. This case series provides the first clinical evidence of intracranial activity of the combination of encorafenib plus binimetinib in patients with BRAF‐mutant melanoma with active brain metastases. Intracranial clinical activity is observed for the first time in patients previously treated with BRAF/MEK inhibitors, a population that has not been previously investigated.

In recent years, a novel small round cell sarcoma harboring EWSR1-NFATC2 translocation with immunomorphologic overlap with Ewing sarcoma (ES), myoepithelial tumors, and extraskeletal myxoid chondrosarcoma has emerged. There has not been a case series devoted to describing its detailed clinicopathologic and immunohistochemical characteristics. Six sarcomas harboring EWSR1-NFATC2 fusion transcripts by reverse transcription polymerase chain reaction and amplification of the fusion gene by fluorescence in situ hybridization were identified. The patients were 5 adult men and 1 adult woman. Three were primary bone tumors of the radius and 3 were primary soft tissue tumors. Most tumors showed monomorphic round to epithelioid cells in anastomosing cords and abundant myxohyaline to collagenous extracellular matrix. Two tumors had large areas of a solid, matrix-poor histomorphology. All tumors stained for CD99 and NKX2.2; while EMA, dot-like cytokeratin, and focal WT-1 and SMA were present in some tumors. All but 1 tumor showed poor histologic and radiologic responses to neoadjuvant ES-specific chemotherapy. Local or distant recurrences happened in 4 cases. EWSR1-NFATC2 sarcoma is a novel translocation-associated sarcoma. It presents as either a primary bone or soft tissue tumor, usually exhibits distinctive histopathologic features, and has predilection for long bones of adult men. It consistently shows recurrent fusion gene amplification readily detectable by EWSR1 breakapart fluorescence in situ hybridization, which serves as a diagnostic surrogate. It has potential for local and distant recurrence and histologic progression, and is resistant to Ewing sarcoma-specific chemotherapy.

Background Plexiform fibromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. These so-called “benign” tumors often present with upper GI bleeding and gastric outlet obstruction. It was recently demonstrated that approximately one-third of PF have activation of the GLI1 oncogene, a transcription factor in the hedgehog (Hh) pathway, via a MALAT1-GLI1 fusion protein or GLI1 up-regulation. Despite this discovery, the biology of most PFs remains unknown. Methods Next generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded (FFPE) samples of PF specimens collected from three institutions (UCSD, NCI and OHSU). Fresh frozen tissue from one tumor was utilized for in vitro assays, including quantitative RT-PCR and cell viability assays following drug treatment. Results Eight patients with PF were identified and 5 patients’ tumors were analyzed by NGS. An index case had a mono-allelic PTCH1 deletion of exons 15–24 and a second case, identified in a validation cohort, also had a PTCH1 gene loss associated with a suspected long-range chromosome 9 deletion. Building on the role of Hh signaling in PF, PTCH1, a tumor suppressor protein, functions upstream of GLI1. Loss of PTCH1 induces GLI1 activation and downstream gene transcription. Utilizing fresh tissue from the index PF case, RT-qPCR analysis demonstrated expression of Hh pathway components, SMO and GLI1, as well as GLI1 transcriptional targets, CCND1 and HHIP. In turn, short-term in vitro treatment with a Hh pathway inhibitor, sonidegib, resulted in dose-dependent cell killing. Conclusions For the first time, we report a novel association between PTCH1 inactivation and the development of plexiform fibromyxoma. Hh pathway inhibition with SMO antagonists may represent a target to study for treating a subset of plexiform fibromyxomas. Electronic supplementary material The online version of this article (10.1186/s12967-019-1995-z) contains supplementary material, which is available to authorized users.

Pediatric mesenchymal tumors harboring variant NTRK fusions (ETV6-negative) are being increasingly described; however, the histologic and clinical features of these variant NTRK tumors and their relationship to classic infantile fibrosarcoma are not well characterized. A better understanding of the clinicopathologic features of these tumors is necessary, and would aid in both early diagnosis and treatment. Therefore, the aim of this study was to characterize a series of pediatric NTRK-rearranged mesenchymal tumors, including classic ETV6-NTRK3 fused tumors and tumors with variant (non-ETV6) NTRK fusions. The clinical features, morphology, immunophenotype, and genetics of 12 classic ETV6-NTRK3 fused infantile fibrosarcoma and 18 variant NTRK-rearranged mesenchymal tumors were evaluated. For both classic and variant groups, the age at diagnosis ranged from birth to 15 years (median, 4 mo) with no sex predilection; the most common sites involved were the extremities and trunk. The rate of local recurrence and metastasis were not significantly different (recurrence rate: 11% classic, 40% variant; metastatic rate: 18% classic, 25% variant). Classic and variant NTRK tumors had an overlapping spectrum of histologic features, containing haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles. Both groups showed diffuse pan-TRK expression by immunohistochemistry. Otherwise, the immunoprofile was nonspecific, but similar between both groups. No statistical difference was seen in any clinicopathologic feature between the classic ETV6-NTRK3 and variant fusion cohorts. Pediatric NTRK-rearranged mesenchymal tumors with both classic and variant fusions likely represent a spectrum of disease with shared, recognizable cliniopathologic features.

Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUCpred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUCtarget). PK from the test dose was then used to calculate a PK-guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUCfirst). A PK-guided first dose resulted in achievement of target AUC with target ranges of ±10% in 50% of patients, ±15% in 75%, and ±20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P = .12, .004, and

Adamantinoma represents a distinct group of bone tumors showing both mesenchymal and epithelial differentiation most commonly involving the tibial diaphysis. Most adamantinomas contain a fibro-osseous component and an epithelial component consisting of squamous or basaloid cells. Adamantinomas are considered malignant neoplasms requiring en bloc excision that frequently recur locally and can rarely metastasize. Rare adamantinomas show an epithelial component consisting predominantly of monomorphic spindle cells, which, combined with an epithelial immunophenotype, can mimic monophasic synovial sarcoma. Synovial sarcoma is very rare in bone. It is considered a high-grade sarcoma that typically necessitates chemotherapy. However, the relationship between spindle cell adamantinoma and intraosseous synovial sarcoma has not been investigated. The current study was prompted by identification of a presumed spindle cell adamantinoma of the tibia with diffuse keratin expression that harbored a SS18 gene region rearrangement. FISH of eight additional bone tumors initially classified as spindle cell adamantinoma based on clinicoradiopathologic findings revealed one additional case with SS18 rearrangement. Histologically, both intraosseous synovial sarcoma and spindle cell adamantinoma demonstrated uniform fusiform nuclei with scant cytoplasm, short fascicles and low mitotic activity. The adamantinomas, but not the synovial sarcomas, were more likely to show overt epithelial differentiation in the form of pseudoglands or squamous nests. Immunohistochemistry of all cases, irrespective of SS18 status, showed diffuse keratin positivity in the spindle cell component, and less consistent EMA positivity. Clinical follow-up was available in both intraosseous synovial sarcomas, one of which recurred and the other metastasized. Two of the six spindle cell adamantinomas with follow-up metastasized. The above findings highlight the morphologic and immunophenotypic overlap between spindle cell adamantinoma and intraosseous synovial sarcoma of the tibia. Investigation of SS18 status to exclude synovial sarcoma is suggested prior to rendering a diagnosis of spindle cell adamantinoma.

Fibroblastic spindle cell tumors are a heterogeneous group of rare soft tissue tumors that are increasingly recognized as associated with a variety of kinase gene fusions. We report two cases of GAB1-ABL1 fusions in spindle cell tumors that histologically overlap with NTRK-rearranged spindle cell tumors. The first case occurred in a 76-year-old female who had a large deep-seated spindle cell tumor composed of monotonous ovoid to spindle cells in a background of thick stromal collagen bands with prominent hyalinized vessels and inconspicuous mitoses (

Metal ion dyshomeostasis and disparate levels of biometals like zinc (Zn), copper (Cu), and selenium (Se) have been implicated as a potential causative factor for Autism Spectrum Disorder (ASD). In this study, we have enrolled 129 children (aged 2–4 years) in North America, of which 64 children had a diagnosis of ASD and 65 were controls. Hair, nail, and blood samples were collected and quantitatively analyzed for Zn, Cu and Se using inductively coupled plasma mass spectrometry (ICP-MS). Of the analyzed biometals, serum Se (116.83 ± 14.84 ng/mL) was found to be significantly lower in male ASD cases compared to male healthy controls (128.21 ± 9.11 ng/mL; p < 0.005). A similar trend was found for nail Se levels in ASD (1.01 ± 0.15 mcg/g) versus that of controls (1.11 ± 0.17 mcg/g) with a p-value of 0.0132 using a stratified Wilcoxon rank sum testing. The level of Se in ASD cohort was co-analyzed for psychometric correlation and found a negative correlation between total ADOS score and serum Se levels. However, we did not observe any significant difference in Zn, Cu, and Zn/Cu ratio in ASD cases versus controls in this cohort of North American children. Further studies are recommended to better understand the biology of the relationship between Se and ASD status.

Highlights: • The Australian Recommended Food Score predicted SMI over 5-years. • A less inflammatory diet and a ‘traditional’ diet predicted SMI over 5-years. • Neither a ‘plant-focused’ nor ‘western’ diet predicted SMI over 5-years., Low muscle mass is associated with reduced independence and increased risk for falls and fractures. Identification of modifiable risk factors for low muscle mass is thus imperative. This study aimed to examine the longitudinal relationship between both diet quality and patterns and lean mass in Australian women. Data from n = 494 participants of the Geelong Osteoporosis Study’s 10- and 15-year women’s follow-ups were used (conducted in 2004–08 and 2011–14, respectively), and participants were aged 21–89 years. Self-reported lifestyle and demographics were collected, and food frequency questionnaire data informed the dietary exposure variables: the Australian Recommended Food Score (ARFS); the Dietary Inflammatory Index (DII); and a posteriori dietary patterns. The outcome, Skeletal Muscle Index (SMI), was calculated from DXA-derived appendicular lean mass (ALM) relative to height (ALM kg/m2). Analyses employed Generalised Estimating Equations. A higher ARFS score positively predicted SMI over 5-years, and adjustments for age and physical activity did not attenuate this relationship (B:0.044, (95%CI 0.004, 0.084) kg/m2). Following adjustment, both an anti-inflammatory diet (B:-0.034, (95%CI −0.070, −0.002) kg/m2) and a ‘traditional’ dietary pattern predicted higher SMI (B:0.081, (95%CI 0.004, 0.158) kg/m2). No other associations were observed. Our study reinforces the importance of diet quality for healthy, aging muscle mass. Furthermore, a less inflammatory diet and a diet comprising a wide variety of plant and animal foods may be conducive to maintenance of muscle mass in women. Further studies investigating diet quality’s impact on various muscle health measures over longer time periods are warranted.

Background Fibrinogen (FIB) levels less than 150 mg/dL have been associated with increased rates of bleeding and lower survival in critically ill cirrhosis patients. Objective We aimed to determine if treatment with cryoprecipitate (CRYO) for low FIB levels is associated with bleeding outcomes or survival. Methods A total of 237 cirrhosis patients admitted to an intensive care unit at a tertiary care liver transplant center with initial FIB levels less than 150 mg/dL were retrospectively assessed for CRYO transfusion, bleeding events, and survival outcomes. Results The mean MELD score was 27.2 (95% confidence interval [CI]: 26.0–28.3) and CLIF-C acute on chronic liver failure score was 53.4 (51.9–54.8). Ninety-nine (41.8%) were admitted for acute bleeding and the remainder were admitted for nonbleeding illnesses. FIB level on admission correlated strongly with disease severity. After adjusting for disease severity, FIB on admission was not an independent predictor of 30-day survival (hazard ratio [HR]: 0.99, 95% CI: 0.99–1.01, p = 0.68). CRYO transfusion increased FIB levels but had no independent effect on mortality or bleeding complications (HR: 1.10, 95% CI: 0.72–1.70, p = 0.65). Conclusion In cirrhosis patients with critical illness, low FIB levels on presentation reflect severity of illness but are not independently associated with 30-day mortality. Treatment of low FIB with CRYO also does not affect survival or bleeding complications, suggesting FIB is an additional marker of severity of illness but is not itself a direct factor in the pathophysiology of bleeding in critically ill cirrhosis patients.

A crucial step towards engineering biological systems is the ability to precisely tune the genetic response to environmental stimuli. In the case of Escherichia coli inducible promoters, our incomplete understanding of the relationship between sequence composition and gene expression hinders our ability to predictably control transcriptional responses. Here, we profile the expression dynamics of 8269 rationally designed, IPTG-inducible promoters that collectively explore the individual and combinatorial effects of RNA polymerase and LacI repressor binding site strengths. We then fit a statistical mechanics model to measured expression that accurately models gene expression and reveals properties of theoretically optimal inducible promoters. Furthermore, we characterize three alternative promoter architectures and show that repositioning binding sites within promoters influences the types of combinatorial effects observed between promoter elements. In total, this approach enables us to deconstruct relationships between inducible promoter elements and discover practical insights for engineering inducible promoters with desirable characteristics., Precisely tuning the genetic response to environmental stimuli is a key step in engineering synthetic biology systems. Here, the authors profile 8269 IPTG-induced promoters to deconstruct the relationship between sequence architecture and gene expression.

Numerous observational studies have investigated the role of the Dietary Inflammatory Index (DII®) in chronic disease risk. The aims of this umbrella review and integrated meta-analyses were to systematically synthesize the observational evidence reporting on the associations between the DII and health outcomes based on meta-analyses, and to assess the quality and strength of the evidence for each associated outcome. This umbrella review with integrated meta-analyses investigated the association between the DII and a range of health outcomes based on meta-analyses of observational data. A credibility assessment was conducted for each outcome using the following criteria: Statistical heterogeneity, 95% prediction intervals, evidence for small-study effect and/or excess significance bias, as well as effect sizes and P values using calculated random effects meta-analyses. In total, 15 meta-analyses reporting on 38 chronic disease-related outcomes were included, incorporating a total population of 4,360,111 subjects. Outcomes (n = 38) were examined through various study designs including case-control (n = 8), cross-sectional (n = 5), prospective (n = 5), and combination (n = 20) study designs. Adherence to a pro-inflammatory dietary pattern had a significant positive association with 27 (71%) of the included health outcomes (P value < 0.05). Using the credibility assessment, Class I (Convincing) evidence was identified for myocardial infarction only, Class II (Highly suggestive) evidence was identified for increased risk of all-cause mortality, overall risk of incident cancer, and risk of incident site-specific cancers (colorectal, pancreatic, respiratory, and oral cancers) with increasing (more pro-inflammatory) DII score. Most outcomes (n = 31) presented Class III (Suggestive) or lower evidence (Weak or No association). Pro-inflammatory dietary patterns were nominally associated with an increased risk of many chronic disease outcomes. However, the strength of evidence for most outcomes was limited. Further prospective studies are required to improve the precision of the effect size. © 2021 The Author(s). Published by Oxford University Press on behalf of the American Society for Nutrition.

The intestinal microbiome has been identified as a key modifier for a variety of health conditions. Fecal Microbiota Transplantation (FMT) has emerged as a fast, safe, and effective means by which to modify the intestinal microbiome and potentially treat a variety of health conditions. Despite extensive research of FMT for CDI, there is a lack of clarity informed by systematic synthesis of data regarding the safety and efficacy of FMT for other health conditions. This systematic review used PRISMA guidelines and was prospectively registered with PROSPERO (CRD42018104243). In March 2020, a search of MEDLINE, EMBASE, and PsycINFO was conducted. We identified 26 eligible studies. A meta-analysis of FMT for active Ulcerative Colitis (UC) showed that FMT significantly improved rates of clinical remission (OR = 3.634, 95% CI = 1.940 to 6.808, I2 = 0%, p

This systematic review and meta-analysis investigated the association between consumption of ultraprocessed food and noncommunicable disease risk, morbidity and mortality. Forty-three observational studies were included (N = 891,723): 21 cross-sectional, 19 prospective, two case-control and one conducted both a prospective and cross-sectional analysis. Meta-analysis demonstrated consumption of ultraprocessed food was associated with increased risk of overweight (odds ratio: 1.36; 95% confidence interval [CI], 1.23-1.51; P < 0.001), obesity (odds ratio: 1.51; 95% CI, 1.34-1.70; P < 0.001), abdominal obesity (odds ratio: 1.49; 95% CI, 1.34-1.66; P < 0.0001), all-cause mortality (hazard ratio: 1.28; 95% CI, 1.11-1.48; P = 0.001), metabolic syndrome (odds ratio: 1.81; 95% CI, 1.12-2.93; P = 0.015) and depression in adults (hazard ratio: 1.22; 95% CI, 1.16-1.28, P < 0.001) as well as wheezing (odds ratio: 1.40; 95% CI, 1.27-1.55; P < 0.001) but not asthma in adolescents (odds ratio: 1.20; 95% CI, 0.99-1.46; P = 0.065). In addition, consumption of ultraprocessed food was associated with cardiometabolic diseases, frailty, irritable bowel syndrome, functional dyspepsia and cancer (breast and overall) in adults while also being associated with metabolic syndrome in adolescents and dyslipidaemia in children. Although links between ultraprocessed food consumption and some intermediate risk factors in adults were also highlighted, further studies are required to more clearly define associations in children and adolescents. STUDY REGISTRATION: Prospero ID: CRD42020176752.

Since the discovery of the ETV6-NTRK3 gene fusion in infantile fibrosarcoma two decades ago, it has become an important diagnostic marker because it is found in the majority of cases. However, the development of new molecular tests, including next generation sequencing, has uncovered additional gene fusions and other oncogenic mutations in tumors with the clinical and morphologic features of infantile fibrosarcoma. We present a case of infantile fibrosarcoma harboring a novel BMPR1A-RAF1 fusion and having a favorable outcome 6 years after surgery. This new structural alteration adds to the list of genetic aberrations in infantile fibrosarcoma and provides another example of the challenge of reconciling classic morphology with novel molecular genetics.

In humans, the 813 G protein-coupled receptors (GPCRs) are responsible for transducing diverse chemical stimuli to alter cell state, and are the largest class of drug targets. Their myriad structural conformations and various modes of signaling make it challenging to understand their structure and function. Here we developed a platform to characterize large libraries of GPCR variants in human cell lines with a barcoded transcriptional reporter of G-protein signal transduction. We tested 7,800 of 7,828 possible single amino acid substitutions to the beta-2 adrenergic receptor (β2AR) at four concentrations of the agonist isoproterenol. We identified residues specifically important for β2AR signaling, mutations in the human population that are potentially loss of function, and residues that modulate basal activity. Using unsupervised learning, we resolve residues critical for signaling, including all major structural motifs and molecular interfaces. We also find a previously uncharacterized structural latch spanning the first two extracellular loops that is highly conserved across Class A GPCRs and is conformationally rigid in both the inactive and active states of the receptor. More broadly, by linking deep mutational scanning with engineered transcriptional reporters, we establish a generalizable method for exploring pharmacogenomics, structure and function across broad classes of drug receptors.

The diagnosis of round cell sarcomas has changed rapidly over the last decade, causing much diagnostic confusion for pathologists and oncologists. The advances in diagnosis are largely due to the advent of next-generation sequencing techniques, which allowed the recognition of novel gene fusions in round cell sarcomas. The new 5th edition of the WHO Classification of Tumors of Soft Tissue and Bone recognizes four subgroups of undifferentiated round cell sarcomas: Ewing sarcoma, CIC-rearranged sarcomas, BCOR-altered sarcomas, and sarcomas with EWSR1-non-ETS fusions, in addition to desmoplastic small round cell tumor. This classification is based on a variety of publications showing that each of these molecular subtypes has unique clinical and prognostic characteristics distinct from Ewing sarcoma, therefore supporting the validity of recognizing these as discrete diagnostic entities. Despite our improved ability to diagnose these new round cell sarcomas, there remains confusion on how best to identify and treat these tumors. However, several key clinicopathologic features can point the physician toward the correct diagnosis. The goal of the following article is to emphasize the key clinical, pathologic, molecular, and prognostic differences between Ewing sarcoma and these non-Ewing round cell malignancies to improve recognition of these rare diseases.

Significant gains have been made in our understanding of bleeding and thrombosis in patients with liver disease in recent years, with concurrent exponential growth in the scientific literature published in this realm. Clinical studies of this population are challenging for multiple reasons including some hurdles unique to this population. Cirrhosis patients as a whole, especially those with decompensated cirrhosis, are a high-risk and heterogeneous population prone to serious adverse events. Outcomes of bleeding and thrombosis are relatively rare and lack standardized, validated definitions. Standard practices for clinical care have evolved rapidly and rendered some control data uninformative. We aim to highlight these challenges and make recommendations for best practices for future study design and implementation. Multidisciplinary collaboration with proceduralists, careful study design including attention to validated clinically relevant outcomes, and aggressive pursuit of all funding streams will be key to continued scientific success in this burgeoning field.

BackgroundOutcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone.MethodsIn this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and 16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients

Multiple digital data streams forecast COVID-19 activity weeks before traditional epidemiological surveillance., Given still-high levels of coronavirus disease 2019 (COVID-19) susceptibility and inconsistent transmission-containing strategies, outbreaks have continued to emerge across the United States. Until effective vaccines are widely deployed, curbing COVID-19 will require carefully timed nonpharmaceutical interventions (NPIs). A COVID-19 early warning system is vital for this. Here, we evaluate digital data streams as early indicators of state-level COVID-19 activity from 1 March to 30 September 2020. We observe that increases in digital data stream activity anticipate increases in confirmed cases and deaths by 2 to 3 weeks. Confirmed cases and deaths also decrease 2 to 4 weeks after NPI implementation, as measured by anonymized, phone-derived human mobility data. We propose a means of harmonizing these data streams to identify future COVID-19 outbreaks. Our results suggest that combining disparate health and behavioral data may help identify disease activity changes weeks before observation using traditional epidemiological monitoring.

Effectively designing and evaluating public health responses to the ongoing COVID-19 pandemic requires accurate estimation of the prevalence of COVID-19 across the United States (US). Equipment shortages and varying testing capabilities have however hindered the usefulness of the official reported positive COVID-19 case counts. We introduce four complementary approaches to estimate the cumulative incidence of symptomatic COVID-19 in each state in the US as well as Puerto Rico and the District of Columbia, using a combination of excess influenza-like illness reports, COVID-19 test statistics, COVID-19 mortality reports, and a spatially structured epidemic model. Instead of relying on the estimate from a single data source or method that may be biased, we provide multiple estimates, each relying on different assumptions and data sources. Across our four approaches emerges the consistent conclusion that on April 4, 2020, the estimated case count was 5 to 50 times higher than the official positive test counts across the different states. Nationally, our estimates of COVID-19 symptomatic cases as of April 4 have a likely range of 2.3 to 4.8 million, with possibly as many as 7.6 million cases, up to 25 times greater than the cumulative confirmed cases of about 311,000. Extending our methods to May 16, 2020, we estimate that cumulative symptomatic incidence ranges from 4.9 to 10.1 million, as opposed to 1.5 million positive test counts. The proposed combination of approaches may prove useful in assessing the burden of COVID-19 during resurgences in the US and other countries with comparable surveillance systems., Author summary Accurate estimates of the weekly incidence of COVID-19 in the United States is essential for planning and researching effective public health responses. Because of systematic testing shortages across the United States, official positive COVID-19 test counts are an unreliable indicator of true incidence. In this study, we present four alternative approaches for estimating cumulative incidence, which leverage different data sources and assumptions. Nationally, our estimates of COVID-19 symptomatic cases as of April 4 have a likely range of 2.3 to 4.8 million, with possibly as many as 7.6 million cases, up to 25 times greater than the cumulative confirmed cases of about 311,000. We emphasize that comparing multiple models rather than relying on a single method gives more reliable estimates of COVID-19 incidence. Our approaches could be useful for tracking the resurgence of COVID-19 in the United States as well as in other countries.

Outbreak to pandemic In response to global dispersion of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), quarantine measures have been implemented around the world. To understand how travel and quarantine influence the dynamics of the spread of this novel human virus, Chinazzi et al. applied a global metapopulation disease transmission model to epidemiological data from China. They concluded that the travel quarantine introduced in Wuhan on 23 January 2020 only delayed epidemic progression by 3 to 5 days within China, but international travel restrictions did help to slow spread elsewhere in the world until mid-February. Their results suggest that early detection, hand washing, self-isolation, and household quarantine will likely be more effective than travel restrictions at mitigating this pandemic. Science , this issue p. 395

Motivated by the rapid spread of a novel coronavirus (2019-nCoV) in Mainland China, we use a global metapopulation disease transmission model to project the impact of both domestic and international travel limitations on the national and international spread of the epidemic. The model is calibrated on the evidence of internationally imported cases before the implementation of the travel quarantine of Wuhan. By assuming a generation time of 7.5 days, the reproduction number is estimated to be 2.4 [90% CI 2.2-2.6]. The median estimate for number of cases before the travel ban implementation on January 23, 2020 is 58,956 [90% CI 40,759 - 87,471] in Wuhan and 3,491 [90% CI 1,924 - 7,360] in other locations in Mainland China. The model shows that as of January 23, most Chinese cities had already received a considerable number of infected cases, and the travel quarantine delays the overall epidemic progression by only 3 to 5 days. The travel quarantine has a more marked effect at the international scale, where we estimate the number of case importations to be reduced by 80% until the end of February. Modeling results also indicate that sustained 90% travel restrictions to and from Mainland China only modestly affect the epidemic trajectory unless combined with a 50% or higher reduction of transmission in the community.

BackgroundAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of three common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are expected to contribute to ASD risk given the high heritability. Here, we performed a genome-wide association study (GWAS) using the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD.MethodsWe performed an association study on 6,222 case-pseudocontrol pairs from SPARK and meta-analyzed with a previous GWAS. We integrated gene regulatory annotations to map non-coding risk variants to their regulated genes. Further, we performed a massively parallel reporter assay (MPRA) to identify causal variant(s) within a novel risk locus.ResultsWe identified one novel GWS locus from the SPARK GWAS. The meta-analysis identified four significant loci, including an additional novel locus. We observed significant enrichment of ASD heritability within regulatory regions of the developing cortex, indicating that disruption of gene regulation during neurodevelopment is critical for ASD risk. The MPRA identified one variant at the novel locus with strong impacts on gene regulation (rs7001340), and expression quantitative trait loci data demonstrated an association between the risk allele and decreased expression of DDHD2 (DDHD domain containing 2) in both adult and pre-natal brains.ConclusionsBy integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.

Brazil detected community transmission of COVID-19 on March 13, 2020. In this study we identified which areas in the country were the most vulnerable for COVID-19, both in terms of the risk of arrival of cases, the risk of sustained transmission and their social vulnerability. Probabilistic models were used to calculate the probability of COVID-19 spread from Sao Paulo and Rio de Janeiro, the initial hotspots, using mobility data from the pre-epidemic period, while multivariate cluster analysis of socio-economic indices was done to identify areas with similar social vulnerability. The results consist of a series of maps of effective distance, outbreak probability, hospital capacity and social vulnerability. They show areas in the North and Northeast with high risk of COVID-19 outbreak that are also highly socially vulnerable. Later, these areas would be found the most severely affected. The maps produced were sent to health authorities to aid in their efforts to prioritize actions such as resource allocation to mitigate the effects of the pandemic. In the discussion, we address how predictions compared to the observed dynamics of the disease.

Mesenchymal round cell tumors are a diverse group of neoplasms defined by primitive, often high-grade cytomorphology. The most common molecular alterations detected in these tumors are gene rearrangements involving EWSR1 to one of many fusion partners. Rare EWSR1-NFATC2 gene rearrangements, corresponding to a t(20;22) gene translocation, have been described in mesenchymal tumors with clear round cell morphology and a predilection for the skeleton. We present a case of a tumor harboring the EWSR1-NFATC2 gene fusion arising in the subcutaneous tissue of a young woman. The tumor exhibited corded and trabecular architecture of epithelioid cells within abundant myxoid and fibrous stroma. The cells showed strong immunoreactivity for NKX2.2, variable CD99, keratin, and epithelial membrane antigen, but were negative for S100 and myoepithelial markers. Importantly, similar to previously reported cases, the clinical course was more indolent than that of Ewing sarcoma. This case highlights the distinctive clinicopathological characteristics of EWSR1-NFATC2 gene fusion-associated neoplasms that distinguish them from Ewing sarcoma.

Achieving hemostasis, preventing and treating thrombosis, and laboratory measurement of the hemostatic pathways constitute the core elements of managing the critically ill patient with liver failure. Uncontrolled bleeding in acutely decompensated cirrhosis and acute-on-chronic liver failure is probably the most familiar clinical challenge to intensivists. Bleeding in these patients can be broadly divided into pressure-driven (portal hypertension-related) bleeding with only limited dependence on hemostatic pathways and intractable mucosal/wound bleeding, which is much more directly related to a severely disturbed hemostatic system with imbalances in the coagulation cascade and the fibrinolytic system. Both types of bleeding can occur simultaneously and may even coexist with inappropriate thrombosis such as portal vein thrombosis or venous thromboembolism. Due to the fundamental role of the liver in coagulation factor synthesis and its direct and indirect regulation of nearly all aspects of the hemostatic system, laboratory measurements of coagulation pathways also constitute key aspects of all prognostic scores that guide clinical decisions and forecast optimal interventions in both acute and chronic forms of liver failure.

Background The highly selective oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib has demonstrated significant activity in adult and pediatric TRK fusion cancers. In the current study, the authors describe the clinical course of children with locally advanced TRK fusion sarcoma who were treated preoperatively with larotrectinib and underwent subsequent surgical resection. Methods A total of 24 children were treated on a pediatric phase 1 trial of larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had a documented TRK fusion sarcoma and underwent surgical resection were included in the current analysis. Tumor response (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively. Results A total of 5 patients (median age, 2 years; range, 0.4-12 years) had locally advanced infantile fibrosarcoma (3 patients) or soft-tissue sarcoma (2 patients). Four patients had disease that was refractory to standard therapy. All 5 patients achieved a partial response to larotrectinib by version 1.1 of RECIST and underwent surgical resection after a median of 6 cycles (range, 4-9 cycles) of treatment. Surgical resections were R0 (negative resection margins with no tumor at the inked resection margin) in 3 patients, R1 (microscopic residual tumor at the resection margin) in 1 patient, and R2 (macroscopic residual tumor at the resection margin) in 1 patient. Three patients achieved complete (2 patients) or near-complete (>98% treatment effect; 1 patient) pathologic responses. These patients remained in follow-up and were no longer receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two patients had viable tumor at the time of surgical resection and positive resection margins and continued to receive adjuvant larotrectinib. No patients experienced postoperative complications or wound healing issues. Conclusions Children with locally advanced TRK fusion sarcomas may proceed to surgical resection after treatment with the selective TRK inhibitor larotrectinib, thereby sparing them the potentially significant morbidity noted with current approaches. These results support the evaluation of larotrectinib as presurgical therapy in children with newly diagnosed TRK fusion sarcomas.

Background: Potassium bromate (KBrO3), a food additive, has been used in many bakery products as an oxidizing agent. It has been shown to induce renal cancer in many in-vitro and in-vivo experimental models. Objectives: This study evaluated the carcinogenic potential of potassium bromate (KBrO3) and the chemopreventive mechanisms of the anti-oxidant and anti-inflammatory phytochemical, curcumin against KBrO3-induced carcinogenicity. Method: Lactate dehydrogenase (LDH) cytotoxicity assay and morphological characteristics were used to assess curcumin's cytoprotective potential against KBrO3 toxicity. To assess the chemopreventive potential of curcumin against KBrO3-induced oxidative insult, intracellular H2O2 and the nuclear concentration of the DNA adduct 8- OHdG were measured. PCR array, qRT-PCR, and western blot analysis were used to identify dysregulated genes by KBrO3 exposure. Furthermore, immunofluorescence was used to evaluate the ciliary loss and the disturbance of cellular tight junction induced by KBrO3. Results: Oxidative stress assays showed that KBrO3 increased the levels of intracellular H2O2 and the DNA adduct 8-OHdG. Combination of curcumin with KBrO3 efficiently reduced the level of H2O2 and 8-OHdG while upregulating the expression of catalase. PCR array, qRT-PCR, and western blot analysis revealed that KBrO3 dysregulated multiple genes involved in inflammation, proliferation, and apoptosis, namely CTGF, IL-1, and TRAF3. Moreover, qRT-PCR and immunofluorescence studies showed that KBrO3 negatively affected the tight junctional protein (ZO-1) and induced a degeneration of primary ciliary proteins. The negative impact of KBrO3 on cilia was markedly repressed by curcumin. Conclusion: Curcumin could potentially be used as a protective agent against carcinogenicity of KBrO3.

BackgroundGene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients.MethodsThis multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (≥16 years of age) or Lansky (

The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18–60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.

Introduction Driving self-regulation is considered a means through which older drivers can compensate for perceived declines in driving skill or more general feelings of discomfort on the road. One form of driving self-regulation is situational avoidance, the purposeful avoidance of situations perceived as challenging or potentially hazardous. This study aimed to validate the Situational Avoidance Questionnaire (SAQ, Davis, Conlon, Ownsworth, & Morrissey, 2016) and identify the point on the scale at which drivers practicing compensatory avoidance behavior could be distinguished from those whose driving is unrestricted, or who are avoiding situations for other, non-compensatory reasons (e.g., time or convenience). Method Seventy-nine Australian drivers (Mage = 71.48, SD = 7.16, range: 55 to 86 years) completed the SAQ and were classified as a compensatory-restricted or a non-restricted driver based on a semi-structured interview designed to assess the motivations underlying avoidance behavior reported on the SAQ. Results Using receiver-operator characteristic (ROC) analysis, the SAQ was found to have high diagnostic accuracy (sensitivity: 85%, specificity: 82%) in correctly classifying the driver groups. Group comparisons confirmed that compensatory-restricted drivers were self-regulating their driving behavior to reduce the perceived demands of the driving task. This group had, on average, slower hazard perception reaction times, and reported greater difficulty with driving, more discomfort when driving due to difficulty with hazard perception skills, and greater changes in cognition over the past five years. Conclusions The SAQ is a psychometrically sound measure of situational avoidance for drivers in baby boomer and older adult generations. Practical applications Use of validated measures of driving self-regulation that distinguish between compensatory and non-compensatory behavior, such as the SAQ, will advance our understanding of the driving self-regulation construct and its potential safety benefits for older road users.

Extended laboratory culture and antimicrobial susceptibility testing timelines hinder rapid species identification and susceptibility profiling of bacterial pathogens associated with bovine respiratory disease, the most prevalent cause of cattle mortality in the United States. Whole-genome sequencing offers a culture-independent alternative to current bacterial identification methods, but requires a library of bacterial reference genomes for comparison. To contribute new bacterial genome assemblies and evaluate genetic diversity and variation in antimicrobial resistance genotypes, whole-genome sequencing was performed on bovine respiratory disease–associated bacterial isolates (Histophilus somni, Mycoplasma bovis, Mannheimia haemolytica, and Pasteurella multocida) from dairy and beef cattle. One hundred genomically distinct assemblies were added to the NCBI database, doubling the available genomic sequences for these four species. Computer-based methods identified 11 predicted antimicrobial resistance genes in three species, with none being detected in M. bovis. While computer-based analysis can identify antibiotic resistance genes within whole-genome sequences (genotype), it may not predict the actual antimicrobial resistance observed in a living organism (phenotype). Antimicrobial susceptibility testing on 64 H. somni, M. haemolytica, and P. multocida isolates had an overall concordance rate between genotype and phenotypic resistance to the associated class of antimicrobials of 72.7% (P < 0.001), showing substantial discordance. Concordance rates varied greatly among different antimicrobial, antibiotic resistance gene, and bacterial species combinations. This suggests that antimicrobial susceptibility phenotypes are needed to complement genomically predicted antibiotic resistance gene genotypes to better understand how the presence of antibiotic resistance genes within a given bacterial species could potentially impact optimal bovine respiratory disease treatment and morbidity/mortality outcomes.

Type 1 Gaucher disease (GD) is the most common lysosomal storage disorder. Previously, treatment for GD was limited to intravenous enzyme replacement therapies (ERTs). More recently, oral substrate reduction therapies (SRTs) were approved for treatment of GD. Although both therapies alleviate disease symptoms, attitudes toward SRTs and patient perceptions of health while using SRT have not been well established. Electronic surveys were administered to adults with GD and asked about treatment history, attitudes toward SRTs, and perception of health while using SRTs as compared to ERTs, if applicable to the participant. ERT users that were offered treatment with SRTs cited potential side effects, wanting more research on SRTs, and satisfaction with their current treatment regimen as reasons for declining SRTs. SRT users expressed convenience and less invasiveness as reasons for choosing SRTs. Additionally, those using SRTs most often perceived their health to be similar to when they previously used ERT. Participant responses illustrate that attitudes toward SRTs can be variable and that one particular treatment may not be ideal for all patients with GD depending on individual perceptions of factors such as convenience, invasiveness, or side effects. Thus, individuals with GD should be counseled adequately by healthcare providers about both ERTs and SRTs for treatment of GD now that SRTs are clinically available.