A highly polymorphic effector protein promotes fungal virulence through suppression of plant-associated Actinobacteria.

Plant pathogens secrete effector proteins to support host colonization through a wide range of molecular mechanisms, while plant immune systems evolved receptors to recognize effectors or their activities to mount immune responses to halt pathogens. Importantly, plants do not act as single organisms, but rather as holobionts that actively shape their microbiota as a determinant of health. The soil-borne fungal pathogen Verticillium dahliae was recently demonstrated to exploit the VdAve1 effector to manipulate the host microbiota to promote vascular wilt disease in the absence of the corresponding immune receptor Ve1. We identify a multiallelic V. dahliae gene displaying c. 65% sequence similarity to VdAve1, named VdAve1-like (VdAve1L), which shows extreme sequence variation, including alleles that encode dysfunctional proteins, indicative of selection pressure to overcome host recognition. We show that the orphan cell surface receptor Ve2, encoded at the Ve locus, does not recognize VdAve1L. Additionally, we demonstrate that the full-length variant VdAve1L2 possesses antimicrobial activity, like VdAve1, yet with a divergent activity spectrum, that is exploited by V. dahliae to mediate tomato colonization through the direct suppression of antagonistic Actinobacteria in the host microbiota. Our findings open up strategies for more targeted biocontrol against microbial plant pathogens.

A phase I study of talazoparib (BMN 673) combined with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782).

BACKGROUND: Inhibitors of poly(ADP-ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel. METHODS: We conducted a phase I study of talazoparib with carboplatin AUC5-6 and paclitaxel 80 mg/m2  days 1, 8, 15 of 21-day cycles in patients with advanced solid tumors. Patients enrolled using a 3 + 3 design in two cohorts with talazoparib for 7 (schedule A) or 3 days (schedule B). After induction with 4-6 cycles of triplet therapy, patients received one of three maintenance options: (a) continuation of triplet (b) carboplatin/talazoparib, or (c) talazoparib monotherapy. RESULTS: Forty-three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment-related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13-month median duration of maintenance. CONCLUSION: We have established the recommended phase II dose of Talazoparib at 250mcg on a 3- or 7-day schedule with carboplatin AUC6 and paclitaxel 80 mg/m2 on days 1, 8, 15 of 21-day cycles. This regimen is associated with significant myelosuppression, and in addition to maximizing supportive care, modification of the chemotherapy component would be a consideration for further development of this combination with the schedules investigated in this study.

Estimating the National Population of Hospitalized Chronic Baclofen Users: A Cross-Sectional Analysis of a Commercial Claims Database.

BACKGROUND: Baclofen is an effective treatment for spasticity. Abrupt cessation of intrathecal (IT) or oral baclofen risks the development of withdrawal symptoms; however, the magnitude of the problem is unknown. OBJECTIVES: The aims for this study were as follows: (1) using an administrative claims database, estimate the number of patients in the United States on baclofen, and (2) estimate the annual percent hospitalized pediatric and adult populations consequently at risk for interruption of chronic baclofen therapy. METHODS: Using 2011-2014 data representing commercially insured individuals, patients were selected based on insurance coverage; evidence of a baclofen claim; and hospitalization. All patients hospitalized while receiving chronic baclofen were assumed to be at risk for baclofen discontinuation. Yearly counts were determined and then extrapolated to national estimates using census data. RESULTS: Extrapolating from the claims database, oral or IT baclofen was prescribed annually to 33,061 or 1486 patients ≤ 18 years, and 654,294 or 7084 patients 19-64 years, respectively. The estimated national mean number of at-risk hospitalizations per year for patients aged 19-64 years on chronic oral or IT baclofen was 31,116 and 3774, respectively; patients ≤ 18 years numbered 4691 and 959, respectively. The mean percent of patients hospitalized per year was 42% in those ≤ 18 years receiving IT baclofen compared with 30% in adults, and 3-10% in the populations receiving oral baclofen. CONCLUSIONS: Extrapolation from an administrative claims database was used to estimate the national number and demographics of hospitalized chronic baclofen users. Patients ≤ 18 years receiving IT baclofen were at highest risk of withdrawal due to a high occurrence of hospitalization.

A survey of Wisconsin pharmacists about cannabinoid products: Are we ready to recommend?

BACKGROUND: In today's culture, cannabis and its cannabinoids are used for both recreational and medicinal purposes. Patients are able to obtain medical and commercial cannabis products. Pharmacists should feel comfortable counseling their patients, given the increased interest, access, and use of these products. OBJECTIVES: The objective of this survey was to assess the familiarity, attitudes, and knowledge of Wisconsin pharmacists regarding products containing cannabinoids. METHODS: An anonymous, Web-based survey was administered to 511 Wisconsin pharmacists using the Pharmacy Practice Enhancement and Action Research Link. The survey was adapted from a nationally developed survey with established validity evidence. Survey items evaluated pharmacists' knowledge of the legality and the pharmacokinetic and pharmacodynamic properties of cannabis. The survey included knowledge (22 items), familiarity (14 items), and attitude (8 items) scales as well as pharmacist demographics and workplace type. Descriptive statistics, Fisher exact test, and Cronbach's alpha were calculated. RESULTS: The survey had a response rate of 19.3%. Nearly 75% of respondents were unfamiliar with the testing practices and pesticide regulations on cannabis production. Pharmacists were also unfamiliar with doses related to commercially available cannabinoid products. A quarter reported that they counsel at least monthly on cannabinoid therapies, but results showed that the majority are uncomfortable with the pharmacology and pharmacotherapy of these compounds. Over two-thirds reported that they need further education on cannabinoids and ranked continuing pharmacy education credits and webinars as their preferred method of learning. Over two-thirds at least somewhat agreed that they would feel comfortable recommending a Food and Drug Administration (FDA)-approved treatment, but a similar proportion reported that they would not recommend non-FDA approved cannabinoid treatments. CONCLUSION: Wisconsin pharmacists require more education to fill knowledge gaps regarding the therapeutic uses of cannabinoid products.

Characterizing Baclofen Withdrawal: A National Survey of Physician Experience.

OBJECTIVE: We studied physicians' opinions and experiences concerning clinical concerns, perceived severity, occurrence, and management of baclofen withdrawal due to abrupt discontinuation. METHODS: A nationwide 26-question electronic survey was distributed via e-mail to physicians (N = 952) representing varying specialties who manage spasticity with baclofen. A total of 110 physicians provided responses to the survey (response rate = 11.6%). Results were evaluated using descriptive statistics. RESULTS: Withdrawal from both oral and intrathecal (IT) baclofen was recognized as a significant concern and was observed by most respondents. However, approximately 75% and 35% of respondents or their clinic sites lack established management protocols for managing anticipated interruption of oral or IT baclofen, respectively. CONCLUSIONS: These findings highlight the need for further research on and the development of guidelines for the prevention and treatment of baclofen withdrawal. The results of this survey, along with a systematic literature review and multidisciplinary stakeholder input, may be helpful in establishing guidelines for the treatment and prevention of baclofen withdrawal.

Interoceptive Sensibility, Alexithymia, and Emotion Regulation in Individuals Suffering from Fibromyalgia.

INTRODUCTION: People suffering from fibromyalgia syndrome report various difficulties in emotional processing, possibly resulting from changes in bodily perception (interoception). In our study, we investigated the relationships between interoceptive sensibility (IS) and two disease-relevant emotional components (alexithymia and emotion regulation) in fibromyalgia sufferers compared to healthy individuals. METHODS: Fifty-five fibromyalgia sufferers and 55 healthy individuals, matched with regard to age and gender, participated in our cross-sectional study. All participants completed the following self-report measures: the Multidimensional Assessment of Interoceptive Awareness, the Toronto Alexithymia Scale, and the Emotion Regulation Skills Questionnaire. Depression and anxiety scores served as confounding variables. RESULTS: Fibromyalgia sufferers reported a stronger tendency to note as well as to avoid (unpleasant) body sensations. IS and psychopathology each explained about thirty percent of the variance in emotion regulation in fibromyalgia sufferers. Alexithymia was related to IS and emotion regulation in controls but not in fibromyalgia sufferers. CONCLUSION: Disturbances in interoception could be seen as the starting point of emotional difficulties in people with fibromyalgia. Following the fear-avoidance-model, experiential avoidance may restrict patients' ability to adaptively regulate emotional states, possibly initiating a vicious cycle of psychological distress and pain.

Pharmacists and the future of cannabis medicine.

OBJECTIVES: To summarize the history and evolution of cannabis use and policies and to review current therapeutic uses, safety, and the central role pharmacists can play. SUMMARY: Cannabis regulation and use have evolved over the centuries and are becoming more widely accepted, with over two-thirds of states in the United States having an approved cannabis program. However, changing policy and a paucity of controlled clinical trials has led to questions on the safety and effectiveness of cannabinoid therapies. Although there are conditions for which cannabinoids may be helpful, potential contraindications, adverse effects, and drug-drug interactions should be taken into account. CONCLUSION: Pharmacists are in a unique position based on their accessibility, knowledge, and skills to guide product selection, dosing, and discuss drug interactions and adverse effects to educate patients on safe cannabis use, whether it be delta-9-tetrahydrocannabinol, cannabidiol, or a combination thereof. Pharmacists and pharmacy organizations, moreover, should advocate for an integral role in the medical cannabis movement to ensure patient safety and evaluate cannabinoid pharmacology, pharmacokinetics, drug-drug interactions, safety, and efficacy through rigorous investigations.

A Randomized Dose Escalation Study of Intravenous Baclofen in Healthy Volunteers: Clinical Tolerance and Pharmacokinetics.

BACKGROUND: Abrupt discontinuation of baclofen can result in a potentially severe withdrawal syndrome. The current treatment for baclofen withdrawal is inadequate, resulting in a critical need to develop an alternative method to prevent or treat this withdrawal syndrome. OBJECTIVE: To evaluate the safety profile and pharmacokinetics of oral (PO) and investigational intravenous (IV) baclofen formulations at clinically relevant doses. DESIGN: Randomized, open-label, dose-escalation, crossover study. SETTING: Contract Research Organization (CRO). METHODS: Three cohorts of 12 healthy adults received single doses of PO baclofen (10 mg, 15 mg or 20 mg) and 10-minute infusions of IV baclofen (7.5 mg, 11.5 mg, or 15 mg) with a minimum 48-hour wash-out period. The third cohort also received a 60-minute infusion of 15 mg IV baclofen after an additional 48-hour wash-out period. MAIN OUTCOME MEASURES: Subjects were observed in a CRO for 24 hours after each dose of baclofen, and were assessed for nystagmus, ataxia, and sedation. Blood samples were collected from 0 to 24 hours and analyzed for baclofen concentration using high-performance liquid chromatography-mass spectroscopy. Noncompartmental pharmacokinetic analyses were performed. Dose linearity and proportionality was assessed using 2-way repeated-measures analysis of variance and a power model analysis. RESULTS: None of the PO or IV doses resulted in significant sedation compared to baseline. All subjects could perform tandem gait after each baclofen dose. The most common side effect, transient mild nystagmus, was noted in 4 of 36 and in 13 of 36 subjects after PO and IV administration, respectively. This was likely related to increased maximum concentrations (Cmax). After the 20 mg PO and 15 mg IV doses, mean Cmax levels were 255 and 722 ng/mL and half-lives were 5.24 and 5.79 hours for PO and IV baclofen, respectively. The mean oral bioavailability for the 20-mg PO dose was approximately 80%. CONCLUSIONS: All PO and IV doses of baclofen were well tolerated clinically. The 80% bioavailability suggests that a 20% reduction in IV dose will produce comparable total drug exposures to that of the PO dose. When PO therapy is interrupted, bridging with IV baclofen may be feasible. LEVEL OF EVIDENCE: II.

Customizing anaphylaxis guidelines for emergency medicine.

BACKGROUND: Most episodes of anaphylaxis are managed in emergency medical settings, where the cardinal signs and symptoms often differ from those observed in the allergy clinic. Data suggest that low recognition of anaphylaxis in the emergency setting may relate to inaccurate coding and lack of a standard, practical definition. OBJECTIVE: Develop a simple, consistent definition of anaphylaxis for emergency medicine providers, supported by clinically relevant consensus statements. DISCUSSION: Definitions of anaphylaxis and criteria for diagnosis from current anaphylaxis guidelines were reviewed with regard to their utilization in emergency medical settings. The agreed-upon working definition is: Anaphylaxis is a serious reaction causing a combination of characteristic findings, and which is rapid in onset and may cause death. It is usually due to an allergic reaction but can be non-allergic. The definition is supported by Consensus Statements, each with referenced discussion. For a positive outcome, quick diagnosis and treatment of anaphylaxis are critical. However, even in the emergency setting, the patient may not present with life-threatening symptoms. Because mild initial symptoms can quickly progress to a severe, even fatal, reaction, the first-line treatment for any anaphylaxis episode--regardless of severity--is intramuscular injection of epinephrine into the anterolateral thigh; delaying its administration increases the potential for morbidity and mortality. When a reaction appears as "possible anaphylaxis," it is generally better to err on the side of caution and administer epinephrine. CONCLUSION: We believe that this working definition and the supporting Consensus Statements are a first step to better management of anaphylaxis in the emergency medical setting.

Evaluating the management of anaphylaxis in US emergency departments: Guidelines vs. practice.

BACKGROUND: Anaphylaxis is characterized by acute episodes of potentially life-threatening symptoms that are often treated in the emergency setting. Current guidelines recommend: 1) quick diagnosis using standard criteria; 2) first-line treatment with epinephrine; and 3) discharge with a prescription for an epinephrine auto-injector, written instructions regarding long-term management, and a referral (preferably, allergy) for follow-up. However, studies suggest low concordance with guideline recommendations by emergency medicine (EM) providers. The study aimed to evaluate how emergency departments (EDs) in the United States (US) manage anaphylaxis in relation to guideline recommendations. METHODS: This was an online anonymous survey of a random sample of EM health providers in US EDs. RESULTS: Data analysis included 207 EM providers. For respondent EDs, approximately 9% reported using agreed-upon clinical criteria to diagnose anaphylaxis; 42% reported administering epinephrine in the ED for most anaphylaxis episodes; and <50% provided patients with a prescription for an epinephrine auto-injector and/or an allergist referral on discharge. Most provided some written materials, and follow-up with a primary care clinician was recommended. CONCLUSIONS: This is the first cross-sectional survey to provide "real-world" data showing that practice in US EDs is discordant with current guideline recommendations for the diagnosis, treatment, and follow-up of patients with anaphylaxis. The primary gaps are low (or no) utilization of standard criteria for defining anaphylaxis and inconsistent use of epinephrine. Prospective research is recommended.

Evaluating the management of anaphylaxis in US emergency departments: Guidelines vs. practice / 世界急诊医学杂志（英文）

@#BACKGROUND: Anaphylaxis is characterized by acute episodes of potentially life-threatening symptoms that are often treated in the emergency setting. Current guidelines recommend: 1) quick diagnosis using standard criteria; 2) first-line treatment with epinephrine; and 3) discharge with a prescription for an epinephrine auto-injector, written instructions regarding long-term management, and a referral (preferably, allergy) for follow-up. However, studies suggest low concordance with guideline recommendations by emergency medicine (EM) providers. The study aimed to evaluate how emergency departments (EDs) in the United States (US) manage anaphylaxis in relation to guideline recommendations. METHODS: This was an online anonymous survey of a random sample of EM health providers in US EDs. RESULTS: Data analysis included 207 EM providers. For respondent EDs, approximately 9%reported using agreed-upon clinical criteria to diagnose anaphylaxis; 42% reported administering epinephrine in the ED for most anaphylaxis episodes; and <50% provided patients with a prescription for an epinephrine auto-injector and/or an allergist referral on discharge. Most provided some written materials, and follow-up with a primary care clinician was recommended. CONCLUSIONS: This is the first cross-sectional survey to provide "real-world" data showing that practice in US EDs is discordant with current guideline recommendations for the diagnosis, treatment, and fol ow-up of patients with anaphylaxis. The primary gaps are low (or no) utilization of standard criteria for defining anaphylaxis and inconsistent use of epinephrine. Prospective research is recommended.

Towards the phylogeny of APS reductases and sirohaem sulfite reductases in sulfate-reducing and sulfur-oxidizing prokaryotes.

The genes for adenosine-5'-phosphosulfate (APS) reductase, aprBA, and sirohaem sulfite reductase, dsrAB, from the sulfur-oxidizing phototrophic bacterium Chromatium vinosum strain D (DSMZ 180(T)) were cloned and sequenced. Statistically significant sequence similarities and similar physicochemical properties suggest that the aprBA and dsrAB gene products from Chr. vinosum are true homologues of their counterparts from the sulfate-reducing chemotrophic archaeon Archaeoglobus fulgidus and the sulfate-reducing chemotrophic bacterium Desulfovibrio vulgaris. Evidence for the proposed duplication of a common ancestor of the dsrAB genes is provided. Phylogenetic analyses revealed a greater evolutionary distance between the enzymes from Chr. vinosum and D. vulgaris than between those from A. fulgidus and D. vulgaris. The data reported in this study are most consistent with the concept of common ancestral protogenotic genes both for dissimilatory sirohaem sulfite reductases and for APS reductases. The aprA gene was demonstrated to be a suitable DNA probe for the identification of apr genes from organisms of different phylogenetic positions. PCR primers and conditions for the amplification of apr homologous regions are described.