Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial.

BACKGROUND: IgA nephropathy is a chronic immune-mediated kidney disease and a major cause of kidney failure worldwide. The gut mucosal immune system is implicated in its pathogenesis, and Nefecon is a novel, oral, targeted-release formulation of budesonide designed to act at the gut mucosal level. We present findings from the 2-year, phase 3 NefIgArd trial of Nefecon in patients with IgA nephropathy. METHODS: In this phase 3, multicentre, randomised, double-blind, placebo-controlled trial, adult patients (aged ≥18 years) with primary IgA nephropathy, estimated glomerular filtration rate (eGFR) 35-90 mL/min per 1·73 m2, and persistent proteinuria (urine protein-creatinine ratio ≥0·8 g/g or proteinuria ≥1 g/24 h) despite optimised renin-angiotensin system blockade were enrolled at 132 hospital-based clinical sites in 20 countries worldwide. Patients were randomly assigned (1:1) to receive 16 mg/day oral capsules of Nefecon or matching placebo for 9 months, followed by a 15-month observational follow-up period off study drug. Randomisation via an interactive response technology system was stratified according to baseline proteinuria (<2 or ≥2 g/24 h), baseline eGFR (<60 or ≥60 mL/min per 1·73 m2), and region (Asia-Pacific, Europe, North America, or South America). Patients, investigators, and site staff were masked to treatment assignment throughout the 2-year trial. Optimised supportive care was also continued throughout the trial. The primary efficacy endpoint was time-weighted average of eGFR over 2 years. Efficacy and safety analyses were done in the full analysis set (ie, all randomly assigned patients). The trial was registered on ClinicalTrials.gov, NCT03643965, and is completed. FINDINGS: Patients were recruited to the NefIgArd trial between Sept 5, 2018, and Jan 20, 2021, with 364 patients (182 per treatment group) randomly assigned in the full analysis set. 240 (66%) patients were men and 124 (34%) were women, and 275 (76%) identified as White. The time-weighted average of eGFR over 2 years showed a statistically significant treatment benefit with Nefecon versus placebo (difference 5·05 mL/min per 1·73 m2 [95% CI 3·24 to 7·38], p<0·0001), with a time-weighted average change of -2·47 mL/min per 1·73 m2 (95% CI -3·88 to -1·02) reported with Nefecon and -7·52 mL/min per 1·73 m2 (-8·83 to -6·18) reported with placebo. The most commonly reported treatment-emergent adverse events during treatment with Nefecon were peripheral oedema (31 [17%] patients, vs placebo, seven [4%] patients), hypertension (22 [12%] vs six [3%]), muscle spasms (22 [12%] vs seven [4%]), acne (20 [11%] vs two [1%]), and headache (19 [10%] vs 14 [8%]). No treatment-related deaths were reported. INTERPRETATION: A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy. Nefecon was also well tolerated, with a safety profile as expected for a locally acting oral budesonide product. FUNDING: Calliditas Therapeutics.

The bone marrow niche from the inside out: how megakaryocytes are shaped by and shape hematopoiesis.

Megakaryocytes (MKs), the largest of the hematopoietic cells, are responsible for producing platelets by extending and depositing long proplatelet extensions into the bloodstream. The traditional view of megakaryopoiesis describes the cellular journey from hematopoietic stem cells (HSCs) along the myeloid branch of hematopoiesis. However, recent studies suggest that MKs can be generated from multiple pathways, some of which do not require transit through multipotent or bipotent MK-erythroid progenitor stages in steady-state and emergency conditions. Growing evidence suggests that these emergency conditions are due to stress-induced molecular changes in the bone marrow (BM) microenvironment, also called the BM niche. These changes can result from insults that affect the BM cellular composition, microenvironment, architecture, or a combination of these factors. In this review, we explore MK development, focusing on recent studies showing that MKs can be generated from multiple divergent pathways. We highlight how the BM niche may encourage and alter these processes using different mechanisms of communication, such as direct cell-to-cell contact, secreted molecules (autocrine and paracrine signaling), and the release of cellular components (eg, extracellular vesicles). We also explore how MKs can actively build and shape the surrounding BM niche.

Risk Stratification for Supratherapeutic Peak Anti-Xa Levels in Adult Patients on Therapeutic Enoxaparin.

BACKGROUND: The American Society of Hematology Guidelines for the management of venous thromboembolism recommend against the use of anti-Xa monitoring for assessing enoxaparin dosing based on a low level of evidence associating supratherapeutic levels with an increased risk of bleeding. However, institutions still utilize anti-Xa levels in select patient populations with altered volume of distribution and/or excretion to monitor and adjust therapy. OBJECTIVE: The primary objective of this study was to identify risk factors associated with supratherapeutic peak anti-Xa levels (≥1.10 IU/mL) for patients receiving therapeutic enoxaparin. METHODS: This was a retrospective single-center study performed at an academic tertiary care hospital. Patients who received enoxaparin at 1 mg/kg twice daily and peak anti-Xa monitoring were separated into supratherapeutic and therapeutic/subtherapeutic cohorts. RESULTS: A total of 436 patients were screened, and 215 were included, with a mean age of 62 years. There were 108 in the therapeutic/subtherapeutic cohort and 107 in the supratherapeutic cohort. Acute kidney injury (AKI), body mass index (BMI), weight, female sex, intensive care unit (ICU) service, Sequential Organ Failure Assessment (SOFA) score ≥4, and creatinine clearance at the time of peak anti-Xa level collection were associated with supratherapeutic anti-Xa levels in univariate models. Adjusted logistic regression models were created and identified BMI in the 30 to 34.9 kg/m2 (odds ratio [OR] 4.35; 95% confidence interval [CI] 1.70-11.13, P < 0.005) and ≥35 kg/m2 (OR 6.75; 95% CI 3.05-14.94, P < 0.005) and AKI (OR 2.62; 95% CI 1.04-6.62, P = 0.042) as significant risk factors for supratherapeutic anti-Xa levels. CONCLUSION AND RELEVANCE: Our study identified BMI ≥ 30 kg/m2, AKI, female sex, ICU service, SOFA score ≥4, and creatinine clearance as risk factors for supratherapeutic anti-Xa levels in patients receiving 1 mg/kg twice daily dosing of enoxaparin. Further research should be done to provide evidence for the association between anti-Xa levels and bleeding risk.

Almond Can Be Infected by Plum Pox Virus-D Isolate Penn4 and Is a Transmission-Competent Host.

Although it is currently eradicated from the United States, Plum pox virus (PPV) poses an ongoing threat to U.S. stone fruit production. Although almond (Prunus dulcis) is known to be largely resistant to PPV, there is conflicting evidence about its potential to serve as an asymptomatic reservoir host for the virus and thus serve as a potential route of entry. Here, we demonstrate that both Tuono and Texas Mission cultivars can be infected by the U.S. isolate PPV Dideron (D) Penn4 and that Tuono is a transmission-competent host, capable of serving as a source of inoculum for aphid transmission of the virus. These findings have important implications for efforts to keep PPV out of the United States and highlight the need for additional research to test the susceptibility of almond to other PPV-D isolates.

Considerable variation in current coronoid height and fracture measurement techniques: a systematic review.

BACKGROUND: Coronoid fractures usually occur in the presence of a significant osseoligamentous injury to the elbow. Fracture size and location correlate with degree of instability and many authors have attempted to analyze the effect of fracture variation on decision making and outcome. There remains no standardized technique for measuring coronoid height or fracture size. The aim of this study was to appraise the literature regarding techniques for coronoid height measurement in order to understand variation. METHODS: Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines were followed. A search was performed to identify studies with either a description of coronoid height, fracture size, or bone loss using the terms (Coronoid) AND (Measurement) OR (Size) OR (Height). Articles were shortlisted by screening for topic relevance based on title, abstract and, if required, full-text review. Exclusion criteria were non-English articles, those on nonhuman species or parts other than the ulna coronoid process, and studies that included patients with pre-existing elbow pathology. Shortlisted articles were grouped based on study type, imaging modality, measurement technique, and measurement parameter as well as its location along the coronoid. RESULTS: Thirty out of the initially identified 494 articles met the inclusion criteria. Twenty-one articles were clinical studies, 8 were cadaveric studies, and 1 combined patients as well as cadavers. A variety of imaging modalities (plain radiographs, 2-dimensional computed tomography [CT], 3-dimensional CT, magnetic resonance imaging or a combination of these) were used with CT scan (either 2-dimensional images or 3-dimensional reconstructions or both) being the most common modality used by 21 studies. Measurement technique also varied from uniplanar linear measurements in 15 studies to multiplanar area and volumetric measurements in 6 studies to techniques describing various angles and indices as an indirect measure of coronoid height in 8 studies. Across the 30 shortlisted studies, 19 different measurement techniques were identified. Fifteen studies measured normal coronoid height while the other 15 measured intact coronoid and/or fracture fragment height. The location of this measurement was also variable between studies with measurements at the apex of the coronoid in 24/30 (80%) of studies. Measurement accuracy was assessed by only 1 study. A total of 12/30 (40%) studies reported on the interobserver and intraobserver reliability of their measurement technique. CONCLUSION: The systemic review demonstrated considerable variability between studies that report coronoid height or fracture size measurements. This variability makes comparison of coronoid height or fracture measurements and recommendations based on these between studies unreliable. There is need for development of a consistent, easy to use, and reproducible technique for coronoid height and bone loss.

Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy.

The therapeutic potential of a novel, targeted-release formulation of oral budesonide (Nefecon) for the treatment of IgA nephropathy (IgAN) was first demonstrated by the phase 2b NEFIGAN trial. To verify these findings, the phase 3 NefigArd trial tested the efficacy and safety of nine months of treatment with Nefecon (16 mg/d) versus placebo in adult patients with primary IgAN at risk of progressing to kidney failure (ClinicalTrials.gov: NCT03643965). NefIgArd was a multicenter, randomized, double-blind, placebo-controlled two-part trial. In Part A, 199 patients with IgAN were treated with Nefecon or placebo for nine months and observed for an additional three months. The primary endpoint for Part A was 24-hour urine protein-to-creatinine ratio (UPCR) after nine months. Secondary efficacy outcomes evaluated included estimated glomerular filtration rate (eGFR) at nine and 12 months and the UPCR at 12 months. At nine months, UPCR was 27% lower in the Nefecon group compared with placebo, along with a benefit in eGFR preservation corresponding to a 3.87 ml/min/1.73 m2 difference versus placebo (both significant). Nefecon was well-tolerated, and treatment-emergent adverse events were mostly mild to moderate in severity and reversible. Part B is ongoing and will be reported on later. Thus, NefIgArd is the first phase 3 IgA nephropathy trial to show clinically important improvements in UPCR and eGFR and confirms the findings from the phase 2b NEFIGAN study.

Telemedicine in sickle cell disease: Patient, parent, and provider perspectives.

INTRODUCTION: Patients with sickle cell disease (SCD) need frequent health maintenance visits and may face barriers accessing care. Telemedicine, during COVID pandemic, has provided a unique model of care to improve access; however, potential barriers and satisfaction with its use in SCD have not been fully evaluated. OBJECTIVE: To determine caregiver, patient, and healthcare provider (HCP) perspectives and satisfaction with telemedicine in healthcare delivery. METHODS: We surveyed patients with SCD, caregivers, and HCP, who participated in at least one telemedicine visit from March 2020 to June 2021, using the Telemedicine Usability Questionnaire (TUQ). We also accessed and compared the Press Ganey surveys completed by families who completed a telemedicine or in-person visit. Data were summarized using descriptive statistics. The internal reliability of TUQ was assessed using Cronbach's coefficient alpha. Press Ganey data comparing satisfaction with telemedicine versus in-person visits were analyzed by Mann-Whiney U test. RESULTS: Fifty-two patients/caregivers and 10 HCP completed the survey. Patients/caregivers rated satisfaction "excellent" in the five areas (Usefulness, Ease of use, Effectiveness, Reliability and Satisfaction). HCP rated Usefulness, Ease of use, Effectiveness, Satisfaction as "good," and Reliability as "excellent." Press Ganey scores for satisfaction with care for telemedicine and in-person visits were not statistically different (p > .05). DISCUSSION: We found high satisfaction for caregivers and patients as well as HCP in the delivery of clinical services via telemedicine for SCD. We suggest that telemedicine is a viable option for this population and may help overcome the barriers SCD families often face accessing care.

Sensitivity and specificity of the posterolateral rotatory drawer test in the diagnosis of lateral collateral ligament insufficiency of the elbow.

BACKGROUND: Numerous clinical tests are described for the diagnosis of chronic lateral collateral ligament (LCL) insufficiency of the elbow; however, none of these tests have been adequately assessed for sensitivity, with at most 8 patients included in previous studies. Furthermore, no test has had specificity assessed. The posterolateral rotatory drawer (PLRD) test is thought to have improved diagnostic accuracy over other tests in the awake patient. The aim of this study is to formally assess this test using reference standards in a large cohort of patients. METHODS: A total of 106 eligible patients were identified for inclusion from a single-surgeon database of operative procedures. Examination under anesthetic (EUA) and arthroscopy were chosen as the reference standards to compare the PLRD test against. Only patients with a clearly documented PLRD test finding performed preoperatively in the clinic, and a clearly documented EUA and/or arthroscopic findings from surgery were included. A total of 102 patients underwent EUA, 74 of whom also underwent arthroscopy. Twenty-eight patients had EUA, and then an open procedure without arthroscopy. Four patients had arthroscopy without a clearly documented EUA. Sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) were calculated with 95% confidence intervals. RESULTS: Thirty-seven patients had a positive PLRD test, and 69 had a negative test. Compared to the reference standard of EUA (n = 102), the PLRD test had a sensitivity of 97.3% (85.8%-99.9%) and a specificity of 98.5% (91.7%-100%) (PPV = 0.973, NPV = 0.985). Compared to the reference standard of arthroscopy (n = 78), the PLRD test had a sensitivity of 87.5% (61.7%-98.5%) and a specificity of 98.4% (91.3%-100%) (PPV = 0.933, NPV = 0.968). Compared to either reference standard (n = 106), the PLRD test has a sensitivity of 94.7% (82.3%-99.4%) and a specificity of 98.5% (92.1%-100%) (PPV = 0.973, NPV = 0.971). CONCLUSION: The PLRD test demonstrated an overall sensitivity of 94.7% and specificity of 98.5% with high positive and negative predictive values. This test is recommended as the primary diagnostic tool for LCL insufficiency in the awake patient and should be widely incorporated into surgical training.

Viral Reservoir Capacity of Wild Prunus Alternative Hosts of Plum Pox Virus Through Multiple Cycles of Transmission and Dormancy.

Plum pox virus (PPV) is a significant pathogen of Prunus worldwide and is known for having a broad experimental host range. Many of these hosts represent epidemiological risks as potential wild viral reservoirs. A comparative study of the PPV reservoir capacity of three commonly found native North American species, western choke cherry (Prunus virginiana var. demissa), black cherry (Prunus serotina), and American plum (Prunus americana) was conducted. Pennsylvania isolates of PPV-D were transmitted from the original host peach (Prunus persica cv. GF305) to all three species. Viral accumulation and transmission rates to alternative hosts and peach were monitored over the course of five vegetative growth and cold induced dormancy (CID) cycles. The three alternative host species demonstrated differences in their ability to maintain PPV-D and the likelihood of transmission to additional alternative hosts or back transmission to peach. Western choke cherry had low (5.8%) initial infection levels, PPV-D was not transmissible to additional western choke cherry, and transmission of PPV-D from western choke cherry to peach was only possible before the first CID cycle. Black cherry had intermediate initial infection levels (26.6%) but did not maintain high infection levels after repeated CID cycles. Conversely, American plum had a high level (50%) of initial infection that was not significantly different from initial infection in peach (72.2%) and maintained moderate levels (15 to 25%) of infection and PPV-D transmission to both American plum and peach through all five cycles of CID. Our results indicate that American plum has the greatest potential to act as a reservoir host for Pennsylvania isolates of PPV-D.

Anticoagulation Considerations in Liver Disease.

Coagulopathy of liver disease is a complex pathology that may result in thrombosis and/or bleeding complications. Routine laboratory values are not always reflective of the degree of these risks. Additionally, prophylaxis and treatment of venous thromboembolism in patients with cirrhosis require careful evaluation when selecting and monitoring drug therapy for these indications. Therefore, this article aims to provide insight regarding coagulopathy of liver disease, influence on laboratory values, and anticoagulant therapy considerations for critical care nurses assuming care for patients with cirrhosis.

Translatome Profiling of Plum Pox Virus-Infected Leaves in European Plum Reveals Temporal and Spatial Coordination of Defense Responses in Phloem Tissues.

Plum pox virus (PPV) is the causative agent of sharka, a devastating disease of stone fruits including peaches, apricots, and plums. PPV infection levels and associated disease symptoms can vary greatly, depending upon the virus strain, host species, or cultivar as well as developmental age of the infected tissues. For example, peaches often exhibit mild symptoms in leaves and fruit while European plums typically display severe chlorotic rings. Systemic virus spread into all host tissues occurs via the phloem, a process that is poorly understood in perennial plant species that undergo a period of dormancy and must annually renew phloem tissues. Currently, little is known about how phloem tissues respond to virus infection. Here, we used translating ribosome affinity purification followed by RNA sequencing to identify phloem- and nonphloem-specific gene responses to PPV infection during leaf development in European plum (Prunus domestica L.). Results showed that, during secondary leaf morphogenesis (4- and 6-week-old leaves), the phloem had a disproportionate response to PPV infection with two- to sixfold more differentially expressed genes (DEGs) in phloem than nonphloem tissues, despite similar levels of viral transcripts. In contrast, in mature 12-week-old leaves, virus transcript levels dropped significantly in phloem tissues but not in nonphloem tissues. This drop in virus transcripts correlated with an 18-fold drop in phloem-specific DEGs. Furthermore, genes associated with defense responses including RNA silencing were spatially coordinated in response to PPV accumulation and were specifically induced in phloem tissues at 4 to 6 weeks. Combined, these findings highlight the temporal and spatial dynamics of leaf tissue responses to virus infection and reveal the importance of phloem responses within a perennial host.

When to Admit to Observation: Predicting Length of Stay for Anticoagulated Elderly Fall Victims.

BACKGROUND: Geriatric patients who fall while taking an anticoagulant have a small but significant risk of delayed intracranial hemorrhage requiring observation for 24 h. However, the medical complexity associated with geriatric care may necessitate a longer stay in the hospital. Little is known about the factors associated with a successful observational status stay (<2 d) for this population. MATERIALS AND METHODS: Elderly patients who fell while taking an anticoagulant admitted from 2012 to 2017 at an ACS level II trauma center were included in a retrospective cohort study to determine what factors were associated with a stay consistent with observational status. INCLUSION CRITERIA: age> 65 y old, negative initial head CT, and one of the following: INR>3.5 if on warfarin, GCS<14, external signs of trauma, or focal neurological deficits. RESULTS: The cohort included 369 patients. Factors associated with decreased likelihood of successful observational status included the need for services after discharge such as an extended care facility (OR 0.06, 95% CI 0.02-0.19, P < 0.001) or visiting nurse agency services (OR 0.27, 95% CI 0.10-0.75, P < 0.001), a dementia diagnosis (OR 0.17, 95% CI 0.04-0.70, P = 0.014), increasing number of medications (OR 0.91, 95% CI 0.84-0.99, P = 0.031), and the use of coumadin (OR 0.28, 95% CI 0.12-0.70, P = 0.006). CONCLUSIONS: For trauma providers, knowing your patient's medication use and particularly type of anticoagulant, comorbidities including dementia, and likely need for services after discharge will help guide the decision to admit the patient for what may be a reasonably lengthy stay versus a brief observation in the hospital for elderly fall victims on anticoagulation.

Reassortment of Genome Segments Creates Stable Lineages Among Strains of Orchid Fleck Virus Infecting Citrus in Mexico.

The genus Dichorhavirus contains viruses with bipartite, negative-sense, single-stranded RNA genomes that are transmitted by flat mites to hosts that include orchids, coffee, the genus Clerodendrum, and citrus. A dichorhavirus infecting citrus in Mexico is classified as a citrus strain of orchid fleck virus (OFV-Cit). We previously used RNA sequencing technologies on OFV-Cit samples from Mexico to develop an OFV-Cit-specific reverse transcription PCR (RT-PCR) assay. During assay validation, OFV-Cit-specific RT-PCR failed to produce an amplicon from some samples with clear symptoms of OFV-Cit. Characterization of this virus revealed that dichorhavirus-like particles were found in the nucleus. High-throughput sequencing of small RNAs from these citrus plants revealed a novel citrus strain of OFV, OFV-Cit2. Sequence comparisons with known orchid and citrus strains of OFV showed variation in the protein products encoded by genome segment 1 (RNA1). Strains of OFV clustered together based on host of origin, whether orchid or citrus, and were clearly separated from other dichorhaviruses described from infected citrus in Brazil. The variation in RNA1 between the original (now OFV-Cit1) and the new (OFV-Cit2) strain was not observed with genome segment 2 (RNA2), but instead, a common RNA2 molecule was shared among strains of OFV-Cit1 and -Cit2, a situation strikingly similar to OFV infecting orchids. We also collected mites at the affected groves, identified them as Brevipalpus californicus sensu stricto, and confirmed that they were infected by OFV-Cit1 or with both OFV-Cit1 and -Cit2. OFV-Cit1 and -Cit2 have coexisted at the same site in Toliman, Queretaro, Mexico since 2012. OFV strain-specific diagnostic tests were developed.

Statistical and practical considerations in designing of immuno-oncology trials.

The novel mechanism of action of immunotherapy agents, in treatment of various types of cancer, poses unique challenges during the designing of clinical trials. It is important to account for possibility of a delayed treatment effect and adjust sample size accordingly. This paper provides an analytical approach for computing sample size in the presence of a delayed effect using a piece-wise proportional hazards model. Failing to account for an anticipated treatment delay may result in considerable loss in power. The overall hazard ratio (HR), which now represents the average HR across the entire treatment period, can remain a meaningful measure of average benefit to patients in the trial. We show that, special consideration needs to be given for the designing of interim analyses related to futility, so as not to increase the probability of incorrectly stopping an effective agent. It is shown that the weighted log-rank test, using the Fleming-Harrington class of weights, can be used as supportive analysis to better reflect the impact of a delayed effect and possible long-term benefit in a subset of the overall population.

MicroRNA-196a is regulated by ER and is a prognostic biomarker in ER+ breast cancer.

BACKGROUND: MicroRNAs are potent post-transcriptional regulators involved in all hallmarks of cancer. Mir-196a is transcribed from two loci and has been implicated in a wide range of developmental and pathogenic processes, with targets including Hox, Fox, Cdk inhibitors and annexins. Genetic variants and altered expression of MIR196A are associated with risk and progression of multiple cancers including breast cancer, however little is known about the regulation of the genes encoding this miRNA, nor the impact of variants therein. METHODS: Genomic data and chromatin interaction analysis were used to discover functional promoter and enhancer elements for MIR196A. Expression data were used to associate MIR196A with mechanisms of resistance, breast cancer subtypes and prognosis. RESULTS: Here we demonstrate that MIR196A displays complex and dynamic expression patterns, in part controlled by long-range transcriptional regulation between promoter and enhancer elements bound by ERα. Expression of this miRNA is significantly increased in drug-resistant models of hormone-receptor positive disease. The expression of MIR196A also proves to be a robust prognostic factor for patients with advanced and post-menopausal ER+ disease. CONCLUSION: This work sheds light on the normal and abnormal regulation of MIR196A and provides a novel stratification method for therapeutically resistant breast cancer.

Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer.

Predicting response to endocrine therapy and survival in oestrogen receptor positive breast cancer is a significant clinical challenge and novel prognostic biomarkers are needed. Long-range regulators of gene expression are emerging as promising biomarkers and therapeutic targets for human diseases, so we have explored the potential of distal enhancer elements of non-coding RNAs in the prognostication of breast cancer survival. HOTAIR is a long non-coding RNA that is overexpressed, promotes metastasis and is predictive of decreased survival. Here, we describe a long-range transcriptional enhancer of the HOTAIR gene that binds several hormone receptors and associated transcription factors, interacts with the HOTAIR promoter and augments transcription. This enhancer is dependent on Forkhead-Box transcription factors and functionally interacts with a novel alternate HOTAIR promoter. HOTAIR expression is negatively regulated by oestrogen, positively regulated by FOXA1 and FOXM1, and is inversely correlated with oestrogen receptor and directly correlated with FOXM1 in breast tumours. The combination of HOTAIR and FOXM1 enables greater discrimination of endocrine therapy responders and non-responders in patients with oestrogen receptor positive breast cancer. Consistent with this, HOTAIR expression is increased in cell-line models of endocrine resistance. Analysis of breast cancer gene expression data indicates that HOTAIR is co-expressed with FOXA1 and FOXM1 in HER2-enriched tumours, and these factors enhance the prognostic power of HOTAIR in aggressive HER2+ breast tumours. Our study elucidates the transcriptional regulation of HOTAIR, identifies HOTAIR and its regulators as novel biomarkers of patient response to endocrine therapy and corroborates the importance of transcriptional enhancers in cancer.

Hypermutation In Pancreatic Cancer.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

Nanopore Sequencing as a Surveillance Tool for Plant Pathogens in Plant and Insect Tissues.

Plant pathogens are constantly emerging and spreading into new areas and there are often limited postdiagnosis treatment options for infection, making surveillance key to their control. Here we present results from a study testing the efficacy of a portable nanopore-based massively parallel sequencing (MPS) technology for use in the detection of diverse plant pathogens in selected samples. The Oxford MinION device was coupled with whole transcriptome amplification (WTA) to sequence the metatranscriptome of plant and insect tissues infected with either Candidatus Liberibacter asiaticus or plum pox virus. Results showed that this methodology is useful for detecting unsuspected viral and bacterial pathogens in plant and insect tissues. The percentage of generated reads assigned to plum pox virus was 95% from infected tissue and 3% from the viruliferous insect, Myzus persicae. Diaphorina citri sequencing led to 22% of the reads mapping as Ca. L. asiaticus. Plum pox virus and Ca. L. asiaticus were detected in both tissue and insect samples near the beginning of each sequencing run, demonstrating the capability of this methodology to obtain results rapidly. This approach also proved the capability of this system to determine the major components of the insect vector's microbiome and the specific strain of small-genome, high-titer pathogens.

Violent Extremism, Community-Based Violence Prevention, and Mental Health Professionals.

New community-based initiatives being developed to address violent extremism in the United States are utilizing mental health services and leadership. This article reviews current approaches to preventing violent extremism, the contribution that mental illness and psychosocial problems can make to violent extremism, and the rationale for integrating mental health strategies into preventing violent extremism. The authors describe a community-based targeted violence prevention model and the potential roles of mental health professionals. This model consists of a multidisciplinary team that assesses at-risk individuals with comprehensive threat and behavioral evaluations, arranges for ongoing support and treatment, conducts follow-up evaluations, and offers outreach, education, and resources for communities. This model would enable mental health professionals in local communities to play key roles in preventing violent extremism through their practice and leadership.