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BackgroundVenous thromboembolism (VTE) is a common morbidity in trauma patients. Standard VTE chemoprophylaxis is often inadequate. We hypothesized that weight-based dosing would result in appropriate prophylaxis more reliably than fixed dosing.MethodsAll patients admitted to a Level 1 trauma center over a 6-month period were included unless contra-indications for VTE prophylaxis existed. A prospective adjusted-dosing group was compared to a retrospective uniform-dosing group. The adjusted-dosing approach consisted of initial weight-based dosing of 0.5 mg/kg subcutaneously (subQ) every 12 h (q12h). Peak anti-factor Xa was measured. Patients outside of the prophylactic range had their dose adjusted by ± 10 mg. The uniform-dosing group received 30 mg subQ q12h, without adjustments.ResultsEighty-four patients were included: 44 in the retrospective control cohort and 40 in the prospective experimental cohort. More patients were sub-prophylactically dosed in the uniform-dosing group relative to the adjusted-dosing group (25% vs 5%, p = 0.03). There was no difference in overall prophylactic range targeting, because the supra-prophylactically dosed patients in the adjusted-dosing group eliminated the effect (p = 0.173). However, after a single dose adjustment, zero patients were outside of prophylactic range (25% versus 0%, RR = infinite, p = 0.003). In the uniform-dosing group, anti-Xa level correlated with body surface area (BSA; R2 = 0.33, p < 0.0001) and weight (R2 = 0.26, p = 0.0005). Weight-based dosing both pre- and post-readjustment normalized the correlation of anti-Xa with BSA (R2 = 0.07, p = 0.1) and weight (R2 = 0.07, p = 0.1).ConclusionsWeight-based VTE prophylaxis with anti-Xa-based dose adjustment improves prophylactic range targeting relative to uniform dosing and eliminates variances secondary to BSA and weight in trauma patients.

Eighteen phorbol and 4-deoxy-4(alpha)-phorbol mono- and diesters have been isolated from croton oil, the seed oil of Croton tiglium L., using a rapid and efficient purification procedure consisting of initial solvent partition followed by droplet counter-current chromatography, reversed-phase chromatography, and preparative thin-layer chromatography. Their structures were determined using physical and spectral characteristics and by hydrolysis and/or synthetic experiments. In this manner, six known long-chain phorbol diesters were isolated, comprising 12-O-decanoylphorbol-13-acetate, 12-O-dodecanoylphorbol-13-acetate, 12-O-tetradecanoylphorbol-13-acetate, 12-O-hexadecanoylphorbol-13-acetate, 12-O-(alpha)-methylbutyrylphorbol-13-decanoate, and 12-O-acetylphorbol-13-decanoate. In addition, five new short-chain phorbol diesters were isolated, namely, 12-O-tiglylphorbol-13-isobutyrate, 12-O-(alpha)-methylbutyrylphorbol-13-isobutyrate, 12-O-tiglylphorbol-13-(alpha)-methylbutyrate, 12-O-tiglylphorbol-13-acetate, and 12-O-(alpha)-methylbutyrylphorbol-13-acetate. A sixth diester obtained, phorbol-12,13-diacetate, has not been isolated previously from any natural source. Two phorbol monoesters were isolated, phorbol-12-tiglate, a new compound, and phorbol-13-acetate, a new natural product. Also isolated were four new 4-deoxy-4(alpha)-phorbol esters, 12-O-tiglyl-4-deoxy-4(alpha)-phorbol-13-isobutyrate, 12-O-tiglyl-4-deoxy-4(alpha)-phorbol-13-acetate, 12-O-(alpha)-methylbutyryl-4-deoxy-4(alpha)-phorbol-13-acetate and 4-deoxy-4(alpha)-phorbol-13-acetate. A complete ('1)H nuclear magnetic spectroscopic assignment of phorbol-12,13,20-triacetate was made using two-dimensional ('1)H-('1)H shift correlation, nuclear Overhauser, and ('1)H-('13)C shift correlation spectroscopies. Evaluation of twenty four croton oil diterpene isolates and derivatives in the in vitro P-388 lymphocytic leukemia and KB nasopharyngeal carcinoma cell bioassay systems revealed 12-O-tetradecanoylphorbol-13-acetate to be the most cytotoxic.

The domestication of cereals has involved common changes in morphological features, such as seed size, seed retention and modification of vegetative and inflorescence architecture that ultimately contributed to an increase in harvested yield1. In barley, this process has resulted in two different cultivated types, two-rowed and six-rowed forms, both derived from the wild two-rowed ancestor, with archaeo-botanical evidence indicating the origin of six-rowed barley early in the domestication of the species, some 8,600–8,000 years ago2. Variation at SIX-ROWED SPIKE 1 (VRS1) is sufficient to control this phenotype. However, phenotypes imposed by VRS1 alleles are modified by alleles at the INTERMEDIUM-C (INT-C) locus. Here we show that INT-C is an ortholog of the maize domestication gene TEOSINTE BRANCHED 1 (TB1) and identify 17 coding mutations in barley TB1 correlated with lateral spikelet fertility phenotypes.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European–American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet’s disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10−9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet’s disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet’s disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet’s spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet’s disease and recurrent aphthous stomatitis.

The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint 1 , 2 . It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity 3 – 5 ; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1 ). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients—emanating from vascular endothelial cells outwards—in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis. NOTCH3 signalling is shown to be the underlying driver of the differentiation and expansion of a subset of synovial fibroblasts implicated in the pathogenesis of rheumatoid arthritis.

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise ‘undruggable’ targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice. Small molecules are identified that inhibit the ubiquitin-specific protease USP7 with high affinity and specificity as explained by co-crystal structures, and are shown to reduce tumour growth in mice. Interfering inhibitors show toxicity to tumours Deubiquitinating enzymes remove the small modifier protein ubiquitin from target substrates regulating their stability. One such enzyme, USP7, is a potential target for anti-cancer therapy, as its inhibition would result in the degradation of the ubiquitinated oncoprotein MDM2, leading to reactivation of the tumour suppressor protein p53. However, selective inhibitors of USP7 have remained elusive. Here, David Komander and colleagues identify two small molecules that inhibit USP7 with high affinity and specificity both in vitro and within cells. The authors provide structural insights into the mechanism of action of these inhibitors and demonstrate their ability to inhibit tumour growth. Elsewhere in this issue, Ingrid Wertz and colleagues independently develop two such USP7 inhibitors and also demonstrate their toxicity towards tumour cells.

The advent of Web-based sports injury surveillance via programs such as the High School Reporting Information Online system and the National Collegiate Athletic Association Injury Surveillance Program has aided the acquisition of football injury data. To describe the epidemiology of injuries sustained in high school football in the 2005-2006 through 2013-2014 academic years and collegiate football in the 2004-2005 through 2013-2014 academic years using Web-based sports injury surveillance. Descriptive epidemiology study. Online injury surveillance from football teams of high school boys (annual average = 100) and collegiate men (annual average = 43). Football players who participated in practices and competitions during the 2005-2006 through 2013-2014 academic years in high school or the 2004-2005 through 2013-2014 academic years in college. Athletic trainers collected time-loss injury (≥24 hours) and exposure data. Injury rates per 1000 athlete-exposures (AEs), injury rate ratios (IRRs) with 95% confidence intervals (CIs), and injury proportions by body site and diagnosis were calculated. The High School Reporting Information Online system documented 18 189 time-loss injuries during 4 539 636 AEs; the National Collegiate Athletic Association Injury Surveillance Program documented 22 766 time-loss injuries during 3 121  476 AEs. The injury rate was higher among collegiate than high school (7.29 versus 4.01/1000 AEs; IRR = 1.82; 95% CI = 1.79, 1.86) athletes. Most injuries occurred during competitions in high school (53.2%) and practices in college (60.9%). The competition injury rate was higher than the practice injury rate among both high school (IRR = 5.62; 95% CI = 5.46, 5.78) and collegiate (IRR = 6.59; 95% CI = 6.41, 6.76) players. Most injuries at both levels affected the lower extremity and the shoulder/clavicle and were diagnosed as ligament sprains and muscle/tendon strains. However, concussion was a common injury during competitions among most positions. Injury rates were higher in college than in high school and higher for competitions than for practices. Concussion was a frequent injury sustained during competitions, which confirms the need to develop interventions to mitigate its incidence and severity.

Key messageThe first cytological characterization of the 2NvS segment in hexaploid wheat; complete de novo assembly and annotation of 2NvS segment; 2NvS frequency is increasing 2NvS and is associated with higher yield.The Aegilops ventricosa 2NvS translocation segment has been utilized in breeding disease-resistant wheat crops since the early 1990s. This segment is known to possess several important resistance genes against multiple wheat diseases including root knot nematode, stripe rust, leaf rust and stem rust. More recently, this segment has been associated with resistance to wheat blast, an emerging and devastating wheat disease in South America and Asia. To date, full characterization of the segment including its size, gene content and its association with grain yield is lacking. Here, we present a complete cytological and physical characterization of this agronomically important translocation in bread wheat. We de novo assembled the 2NvS segment in two wheat varieties, ‘Jagger’ and ‘CDC Stanley,’ and delineated the segment to be approximately 33 Mb. A total of 535 high-confidence genes were annotated within the 2NvS region, with > 10% belonging to the nucleotide-binding leucine-rich repeat (NLR) gene families. Identification of groups of NLR genes that are potentially N genome-specific and expressed in specific tissues can fast-track testing of candidate genes playing roles in various disease resistances. We also show the increasing frequency of 2NvS among spring and winter wheat breeding programs over two and a half decades, and the positive impact of 2NvS on wheat grain yield based on historical datasets. The significance of the 2NvS segment in wheat breeding due to resistance to multiple diseases and a positive impact on yield highlights the importance of understanding and characterizing the wheat pan-genome for better insights into molecular breeding for wheat improvement.

The Cystic Fibrosis (CF) Foundation developed clinical care guidelines for the prevention of Pseudomonas aeruginosa infection, the treatment of initial P. aeruginosa infection, and the use of bronchoscopy to obtain routine airway cultures in individuals with CF. A multidisciplinary committee developed questions about the prevention and treatment of initial P. aeruginosa infection and the use of bronchoscopy to obtain routine airway cultures. The outcome measure of interest was cultures without P. aeruginosa growth. Systematic reviews of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were conducted in May 2012 and August 2013. Searches combined controlled vocabulary terms and text words for CF and terms relevant to each question. The entire committee reviewed the evidence, and final recommendation statements were graded using the U.S. Preventive Services Task Force system. Recommendation 1: The CF Foundation strongly recommends inhaled antibiotic therapy for the treatment of initial or new growth of P. aeruginosa from an airway culture (certainty of net benefit, high; estimate of net benefit, substantial; grade of recommendation, A). The favored antibiotic regimen is inhaled tobramycin (300 mg twice daily) for 28 days. Recommendation 2: The CF Foundation recommends against the use of prophylactic antipseudomonal antibiotics to prevent the acquisition P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, zero; grade of recommendation, D). Recommendation 3: The CF Foundation recommends routine oropharyngeal cultures rather than bronchoalveolar lavage cultures obtained by bronchoscopy in individuals with CF who cannot expectorate sputum to determine if they are infected with P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, moderate; grade of recommendation, B).