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Objective: Intravenous (IV) push (IVP) is an alternative administration method for levetiracetam, but evidence evaluating it compared to IV piggyback (IVPB) for loading doses in acutely seizing patients is limited, particularly in patients with status epilepticus (SE). This study aimed to compare the efficiency and safety of IVP versus IVPB levetiracetam loading doses. Methods: This was a single‐center sequential retrospective study conducted in adult (≥18 years) patients who received an IV levetiracetam loading dose (>2000 mg or ≥20 mg/kg) for acute or suspected seizure. The primary outcome was time to administration, compared between doses given as IVP versus IVPB. Secondary outcomes included rates of adverse events (AEs), rescue benzodiazepine or antiseizure medication administration, intubation, and intensive care unit (ICU) admission between groups. Results: A total of 246 patients were included; 116 received IVP and 130 received IVPB loading doses. Median age was 56 years; most patients were male (62%) and White (60%) and had witnessed seizures (67%). Doses were administered for SE in 32 (27.5%) and 46 (35.4%) patients in the IVP and IVPB arms, respectively. Median time to administration was shorter in the IVP group (12 vs. 38 min, p <.001). Bradycardia (1.7% vs. 2.3%, p =.99), hypotension (7.8% vs. 12%, p =.30), sedation (6% vs. 12.3%, p =.09), intubation (10% vs. 8%, p =.37), ICU admission (32% vs. 39%, p =.31), and rescue medication administration (8.6% vs. 14.6% p =.10) were similar between groups. In SE patients, IVP was associated with shorter time to administration (12 vs. 44 min, p =.003) and lower odds of ICU admission after adjustment for age, dose, Status Epilepticus Severity Score, and seizure history (adjusted odds ratio =.23, 95% confidence interval =.06–.81). Significance: IVP reduced time to levetiracetam administration versus IVPB and was not associated with more AEs. Rescue agent use, intubation, and ICU admission were similar between arms, but IVP may reduce ICU admissions in SE patients. Prospective studies should assess the effectiveness of IVP versus IVPB. [ABSTRACT FROM AUTHOR]

Bromocriptine is a dopamine receptor agonist used for central hyperthermia with limited data. We describe our single-center experience utilizing bromocriptine for central hyperthermia, including the population treated, most common dosing regimens, adverse events, and discontinuation reasons. A retrospective study was conducted screening patients who were admitted to intensive care units for acute neurological insults and administered bromocriptine for central hyperthermia between April 2016 and September 2022. Baseline characteristics, disease severity markers, and bromocriptine doses were collected. Body temperatures prior to the first dose of bromocriptine, at the time of dose, and after each dose were recorded. Co-administration of additional hyperthermia management therapies was noted. Thirty patients were included. The most common diagnosis was traumatic brain injury (TBI) (N = 14). The most common reason for discontinuation was resolution of indication (N = 14). Discontinuation due to mild adverse effects occurred in four patients; hepatotoxicity was the most common. There was a paired mean difference of −0.37°C (p = 0.005) between temperatures before and after bromocriptine initiation. Bromocriptine is a potential therapy for the management of central hyperthermia in patients with severe acute neurologic insults who have failed other therapies. Bromocriptine was well tolerated and associated with a low incidence of adverse events. [ABSTRACT FROM AUTHOR]

Chronic complications are a significant concern for people living with HIV/AIDS (PLWHA) infection. HIV-associated neurocognitive disorders (HAND) are prevalent in PLWHA. Yet, the efficacy of medications that penetrate the central nervous system (CNS) at preventing or slowing the progression of HAND remains largely unknown. The objective of this study was to determine whether high CNS penetration effectiveness (CPE) regimens improve neurocognitive test scores in PLWHA on combined antiretroviral therapy (cART). Primary literature evaluating cognitive outcomes based on CPE score of cART regimens in PLWHA was assembled from PubMed/Medline and EMBASE. Both randomized controlled trials and observational studies with at least 12 weeks of follow-up were included. A meta-analysis was conducted to calculate the standardized mean difference. Eight trials including a total of 3,303 patients with 13,103 person-years of follow-up were included in the systematic review. Four trials (n = 366 patients) met our inclusion criteria and were included in the meta-analysis. In the meta-analysis, HIV regimens with a high CPE score did not affect NPZ-4 or GDS scores (standardized mean difference (SMD) 0.10, 95% CI −0.19, 0.38; I2 = 26%). Future studies with larger sample sizes are warranted to prospectively evaluate the relationship between CPE and progression of HAND. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, as well as the nitrate-nitrite-NO pathway. The three isoforms of NOS, namely neuronal (NOS1), inducible (NOS2), and endothelial (NOS3), have different localisation and functions in the human body, and are consequently thought to have differing pathophysiological roles. Furthermore, as we continue to develop a deepened understanding of the different roles of NOS isoforms in disease, the possibility of therapeutically modulating NOS activity has emerged. Indeed, impaired (or dysfunctional), as well as overactive (or dysregulated) NOS activity are attractive therapeutic targets in cardiovascular disease. This review aims to describe recent advances in elucidating the physiological role of NOS isoforms within the cardiovascular system, as well as mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease. We then discuss the modulation of NO and NOS activity as a target in the development of novel cardiovascular therapeutics. [ABSTRACT FROM AUTHOR]

Introduction/Aims: High‐risk medication exposure is a modifiable risk factor for myasthenic exacerbation and crisis. We evaluated whether real‐time electronic clinical decision support (CDS) was effective in reducing the rate of prescribing potentially high‐risk medications to avoid or use with caution in patients with myasthenia gravis. Methods: An expert panel reviewed the available drug‐disease pairings and associated severity levels to activate the alerts for CDS. All unique alerts activated in both inpatient and outpatient contexts were analyzed over a two‐year period. Clinical context, alert severity, medication class, and alert action were collected. The primary outcome was alert override rate. Secondary outcomes included the percentage of unique medication exposures avoided and predictors of alert override. Results: During the analysis period, 2817 unique alerts fired, representing 830 distinct patient‐medication exposures for 577 unique patients. The overall alert override rate was 85% (80.3% for inpatient alerts and 95.8% for outpatient alerts). Of unique medication‐patient exposures, 19% were avoided because of the alert. Assigned alert severity of "contraindicated" were less likely to be overridden (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.32–0.56), as well as alerts activated during evening staffing (OR 0.69, 95% CI 0.55–0.87). Discussion: Implementation of a myasthenia gravis drug‐disease interaction alert reduced overall patient exposure to potentially harmful medications by approximately 19%. Future optimization includes enhanced provider and pharmacist education. Further refinement of alert logic criteria to optimize medication risk reduction and reduce alert fatigue is warranted to support clinicians in prescribing and reduce electronic health record time burden. [ABSTRACT FROM AUTHOR]

We review pharmacological/prescribing principles relating to metformin according to our mnemonic framework: 'BRAINS & AIMS' (Benefits, Risks, Adverse Effects, Interactions, Necessary prophylaxis, Susceptibilities, Administering, Informing, Monitoring and Stopping): Benefits: Metformin's licensed uses: Type 2 diabetes mellitus (T2DM) treatment, reduction in risk or delay of onset. No clear evidence metformin influences patient‐important outcomes [Cochrane Review (2020) of 18 RCTs (n = 10 680)]. Risks: Inexpensive, essential WHO list drug; use contraindicated/not tolerated in 15%: for example, contraindication: lactic acidosis in renal impairment (eGFR <30 mL/min/1.73 m2). Adverse effects: Common gastrointestinal (GI) side effects are dose‐related and include abdominal pain, decreased appetite, diarrhoea (usually transient), nausea and vomiting, altered taste; vitamin B12 deficiency. Rare: acute metabolic acidosis (lactic acidosis/diabetic ketoacidosis). Interactions (pharmacokinetic) occur with drugs impairing renal function and hence metformin excretion, and drugs inhibiting organic cation transporter 1 or 2 (OCT1, OCT2), and/or multidrug and toxin extrusion protein 1 (MATE1/2‐K), such as cimetidine, ranolazine, trimethoprim and verapamil, and inducers such as rifampicin. The risk of hypoglycaemia may increase when metformin is used in combination with other medications for diabetes (pharmacodynamic interaction). Necessary prophylaxis: Detect/treat vitamin B12 deficiency. Susceptible groups: Elderly/renal/liver impairment (lactic acidosis); safe in pregnancy/breastfeeding. Administering: Initially 500 mg once daily (morning) with breakfast; titrate only after 1 week. Informing (relevant BRAINS & A(I)MS principles). Monitoring: Renal function beforehand, and 6–12 monthly, HbA1c 3–6 monthly until controlled. Serum vitamin B12 levels if deficiency is suspected/risk factors for. Stopping: Encourage patients to continue medication, unless deteriorating renal/liver function. Reasons for deprescribing: no harms from stopping suddenly. [ABSTRACT FROM AUTHOR]

Background: Bedside percutaneous dilatational tracheostomy (PDT) and percutaneous endoscopic gastrostomy (PEG) are common procedures performed in the intensive care unit (ICU). Venous thromboembolism (VTE) prophylaxis is frequently prescribed to ICU patients and it remains unclear whether pre-procedure discontinuation is necessary. Methods: This multi-center prospective observational study aimed to describe bleeding rates in patients undergoing bedside PEG or PDT who did or did not have VTE prophylaxis held. Decision to hold prophylaxis was made by the operating physician. The primary endpoint was the rate of peri-procedural bleeding complications. Secondary endpoints included quantification of held doses in the peri-procedural period, rate of venous thromboembolism, and characteristics associated with having prophylaxis held. Results: 91 patients were included over a 2-year period. Patients were on average aged 54 years, 40% female, mostly admitted to the trauma service (59%), and most commonly underwent bedside PDT (59%). Overall, 21% of patients had doses of pre-procedure prophylaxis held. Bleeding events occurred in 1 patient (1.4%) who had prophylaxis continued and in 1 patient (5.0%) who had prophylaxis held, a rate difference of 3.6% (95% CI–9.5%, 16.7%). One bleeding event was managed with bedside surgical repair and one with blood transfusion. There were 10 VTE events, all of whom had prophylaxis continued during the pre-procedure period but 3 had prophylaxis held after the procedure. Conclusions: Bleeding complications were rare and did not significantly differ depending on whether prophylaxis was held or not. Future research is required to confirm the lack of risk with continuing prophylaxis through bedside procedures. [ABSTRACT FROM AUTHOR]

Introduction: Antibiotic-resistant Gram-negative bacteria have been associated with substantial morbidity and mortality and have limited treatment options available. Omadacycline (OMC) is an aminomethylcycline antibiotic that has been shown to exhibit broad in vitro activity against antibiotic-resistant Gram-negative bacteria. Given the lack of real-world data, the primary objective of our report was to describe early experience with OMC for the treatment of resistant Gram-negative infections. Methods: This was a real-world, multicenter, observational cases series/pilot study conducted in the USA. Inclusion criteria included any adult patient aged ≥ 18 years who received OMC for ≥ 72 h either in the inpatient and/or outpatient setting. Clinical success was defined as a composite of 90-day survival from initiation of OMC, lack of alteration in treatment/addition of other antibiotic due to concerns of OMC failure, and lack of microbiologic recurrence within 30 days from the end of therapy. Results: Oral OMC was used in nine cases primarily for multidrug-resistant (MDR)/extensively drug-resistant (XDR) Gram-negative bacterial infections (55.6% XDR and/or carbapenem-resistant Acinetobacter baumannii [CRAB]). The majority of infections were of bone/joint (55.6%) origin, followed by intra-abdominal (33.3%) origin. Clinical success occurred in 66.7% of cases, with 80.0% success each in infections of bone/joint origin or those caused by CRAB. One patient experienced an adverse effect that was not treatment limiting while on therapy (gastrointestinal). Conclusion: The use of oral OMC in MDR/XDR Gram-negative infections exhibited a relatively high success rate with minimal adverse effects. Real-world studies with larger case numbers are needed to confirm our initial findings. [ABSTRACT FROM AUTHOR]

Background: Coagulopathy in traumatic brain injury (TBI) is associated with increased risk of poor outcomes, but accurate prediction of clinically significant progressive hemorrhagic injury (PHI) in patients with severe TBI remains a challenge. Thromboelastography (TEG) is a real-time test of whole blood coagulation that provides dynamic information about global hemostasis. This study aimed to identify differences in TEG values between patients with severe TBI who did or did not experience clinically significant PHI. Methods: This was a single-center retrospective cohort study of adult patients with severe TBI. Patients were eligible for inclusion if initial Glasgow coma scale (GCS) was ≤ 8 and baseline head computed tomography (CT) imaging and TEG were available. Exclusion criteria included receipt of hemostatic agents prior to TEG. PHI was defined as bleeding expansion on CT within 24 h associated with 2-point drop in GCS, neurosurgical intervention, or mortality within 24 h. The primary endpoint was TEG value differences between patients with and without PHI. Secondary endpoints included differences in conventional coagulation tests (CCTs) between groups. Results: Of the 526 patients evaluated, 141 met inclusion criteria. The most common reason for exclusion was lack of baseline TEG and receipt of reversal product prior to TEG. Sixty-four patients experienced PHI in the first 24 h after presentation. K time (2.03 min vs. 1.33 min, P = 0.035) and alpha angle (65° vs. 69°, P = 0.015) were found to be significantly different in patients experiencing PHI. R time (5.25 min vs. 4.71 min), maximum amplitude (61 mm vs. 63 mm), and clot lysis at 30 min after maximum clot strength (3.5% vs. 1.7%) were not significantly different between groups. Of the CCTs, only activated partial thromboplastin time (30.3 s vs. 27.6 s, P = 0.014) was found to be different in patients with PHI. Conclusions: Prolonged K time and narrower alpha angle were found to be associated with developing clinically significant PHI in patients with severe TBI. Despite differences detected in alpha angle, median values in both groups were within normal reference ranges. These abnormalities may reflect pathologic hypoactivity of fibrinogen, and further study is warranted to evaluate TEG-guided cryoprecipitate administration in this patient population. [ABSTRACT FROM AUTHOR]

Aims: To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, vs. placebo/doxazosin, to control for blood pressure (BP). Methods: A subgroup of participants in our double‐blind, randomized‐controlled, factorial VaSera trial had carotid imaging. Patients with hypertension and with/at risk of type 2 diabetes were randomized to active nitrate‐containing beetroot juice or placebo nitrate‐depleted juice, and spironolactone or doxazosin. Vascular ultrasound for carotid diameter (CD, mm) and intima–media thickness (CIMT, mm) was performed at baseline, 3‐ and 6‐months. Carotid local stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph) and carotid lumen area. Data were analysed by modified intention to treat and using mixed‐model effect, adjusted for confounders. Results: In total, 93 subjects had a baseline evaluation and 86% had follow‐up data. No statistical interactions occurred between the juice and drug arms and BP was similar between the juices and between the drugs. Nitrate‐containing vs. placebo juice significantly lowered CIMT (−0.06 [95% confidence interval −0.12, −0.01], P =.034), an overall difference of ~8% relative to baseline; but had no effect on CD or CS. Doxazosin appeared to reduce CS from baseline (−0.34 [−0.62, −0.06]) however, no difference was detected vs. spironolactone (−0.15 [−0.46, 0.16]). No differences were detected between spironolactone or doxazosin on CIMT and CD. Conclusions: Our results show that 6 months' intervention with dietary nitrate influences vascular remodelling, but not carotid stiffness or diameter. Neither spironolactone nor doxazosin had a BP‐independent effect on carotid structure and function. [ABSTRACT FROM AUTHOR]

Inorganic nitrite is a source of nitric oxide (NO) and is considered as a potential therapy in settings where endogenous NO bioactivity is reduced and left ventricular (LV) function impaired. However, the effects of nitrite on human cardiac contractile function, and the extent to which these are direct or indirect, are unclear. We studied 40 patients undergoing diagnostic cardiac catheterization who had normal LV systolic function and were not found to have obstructive coronary disease. They received either an intracoronary sodium nitrite infusion (8.7-26 mmol/min, n = 20) or an intravenous sodium nitrite infusion (50 mg/kg/min, n = 20). LV pressure-volume relations were recorded. The primary end point was LV end-diastolic pressure (LVEDP). Secondary end points included indices of LV systolic and diastolic function. Intracoronary nitrite infusion induced a significant reduction in LVEDP, LV end-diastolic pressure-volume relationship (EDPVR), and the time to LV end-systole (LVEST) but had no significant effect on LV systolic function or systemic hemodynamics. Intravenous nitrite infusion induced greater effects, with significant decreases in LVEDP, EDPVR, LVEST, LV dP/dtmin, tau, and mean arterial pressure. Inorganic nitrite has modest direct effects on human LV diastolic function, independent of LV loading conditions and without affecting LV systolic properties. However, the systemic administration of nitrite has larger effects on LV diastolic function, which are related to reduction in both preload and afterload. These contractile effects of inorganic nitrite may indicate a favorable profile for conditions characterized by LV diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Background: Twitter has emerged as a powerful networking and educational tool within the health care community. The instantaneous and casual nature of Twitter allows for easy access to a near limitless pool of medical professionals and the opportunity to share intra‐ and interprofessional knowledge. Beyond individual development, Twitter has the potential to positively impact pharmacy residency programs in a multitude of ways. Objective: This article serves as a practical guide for pharmacy residency programs to implement and maintain a successful Twitter account. Recommendations At the program level, a Twitter account creates an official voice and brand while simultaneously providing detail and perspective beyond what a residency website may offer. Additionally, it allows for dynamic ground‐level engagement with prospective residency candidates, current residents, and preceptors which is mutually beneficial to the program audience. In the age of virtual recruitment, successfully utilizing digital tools to meet candidates where they are is essential for attracting the right candidate for the program. Implementation of a successful social media strategy has potential barriers that include garnering buy‐in from departmental leadership, operationalizing a social media team, and maintaining engagement momentum. Conclusion: Pharmacy residency programs should consider starting an official Twitter account. [ABSTRACT FROM AUTHOR]

Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2–11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy. [ABSTRACT FROM AUTHOR]

Aims: Dietary nitrate from sources such as beetroot juice lowers blood pressure (BP) via the nitrate–nitrite–nitric oxide (NO) pathway. However, NO and nitrite are inactivated via reoxidation to nitrate, potentially limiting their activity. Cytochrome P450‐3A4 inhibition with troleandomycin prevents nitrite re‐oxidation to nitrate in rodent liver. Grapefruit juice contains the CYP3A4 inhibitor furanocoumarin. We therefore hypothesized that grapefruit juice would enhance BP‐lowering with beetroot juice by maintaining circulating [nitrite]. Methods: We performed a randomized, placebo‐controlled, 7‐hour crossover study in 11 healthy volunteers, attending on 3 occasions, receiving: a 70‐mL shot of active beetroot juice (Beet‐It) and either (i) 250 mL grapefruit juice (Active Beet+GFJ), or (ii) 250 mL water (Buxton, Active Beet+H2O); or (iii) Placebo Beet+GFJ. Results: The addition of grapefruit juice to active beetroot juice lowered systolic BP (SBP): Active Beet+GFJ vs Active Beet+H2O (P =.02), and pulse pressure, PP (P =.0003). Peak mean differences in SBP and PP were seen at T = 5 hours: −3.3 mmHg (95% confidence interval [CI] −6.43 to −0.15) and at T = 2.5 hours: −4.2 mmHg (95% CI −0.3 to −8.2), respectively. Contrary to the hypothesis, plasma [nitrite] was lower with Active Beet+GFJ vs Active Beet+H2O (P =.006), as was salivary nitrite production (P =.002) and saliva volume (−0.34 mL/min [95% CI −0.05 to −0.68]). The taste score of Beet+GFJ was 1.4/10 points higher than Beet+H2O (P =.03). Conclusion: Grapefruit juice enhanced beetroot juice's effect on lowering SBP and PP despite decreasing plasma [nitrite]. Besides suggesting more complex mechanisms, there is potential for maximising the clinical benefit of dietary nitrate and targeting isolated systolic hypertension. [ABSTRACT FROM AUTHOR]

Aims: To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure. Methods: Daily spironolactone (≤50 mg) vs doxazosin (control ≤16 mg) and 70 mL beetroot juice (Beet‐It ≤11 mmol nitrate) vs nitrate‐depleted juice (placebo; 0 mmol nitrate) were tested in people at risk or with type‐2 diabetes using a double‐blind, 6‐month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac–ankle vascular index (CAVI), a nominally pressure‐independent stiffness measure (primary outcome), PWVart secondary, central systolic pressure and augmentation. Analysis was intention‐to‐treat, adjusted for systolic pressure differences between trial arms. Results: Spironolactone did not reduce stiffness, with evidence for reduced CAVI on doxazosin rather than spironolactone (mean difference [95% confidence interval]; 0.25 [−0.3, 0.5] units, P =.080), firmer for PWVart (0.37 [0.01, 0.7] m/s, P =.045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7 [−4.8, 3.3] mmHg, P =.7). Circulating nitrate and nitrite increased on active vs placebo juice, with central systolic pressure lowered −2.6 [−4.5, − 0.8] mmHg, P =.007 more on the active juice, but did not reduce CAVI, PWVart or peripheral pressure. Change in nitrate and nitrite concentrations were 1.5‐fold [1.1–2.2] and 2.2‐fold [1.3, 3.6] higher on spironolactone than on doxazosin respectively; both P <.05. Conclusion: Contrary to our hypothesis, in at‐risk/type 2 diabetes patients, spironolactone did not reduce arterial stiffness, rather PWVart was lower on doxazosin. Dietary nitrate elevated plasma nitrite, selectively lowering central systolic pressure, observed previously for nitrite. [ABSTRACT FROM AUTHOR]

Aims: Dietary inorganic nitrate (NO3−) lowers peripheral blood pressure (BP) in healthy volunteers, but lacks such effect in individuals with, or at risk of, type 2 diabetes mellitus (T2DM). Whilst this is commonly assumed to be a consequence of chronic hyperglycaemia/hyperinsulinaemia, we hypothesized that acute physiological elevations in plasma [glucose]/[insulin] blunt the haemodynamic responses to NO3−, a pertinent question for carbohydrate‐rich Western diets. Methods: We conducted an acute, randomized, placebo‐controlled, double‐blind, crossover study on the haemodynamic and metabolic effects of potassium nitrate (8 or 24 mmol KNO3) vs. potassium chloride (KCl; placebo) administered 1 hour prior to an oral glucose tolerance test in 33 healthy volunteers. Results: Compared to placebo, there were no significant differences in systolic or diastolic BP (P = 0.27 and P = 0.30 on ANOVA, respectively) with KNO3, nor in pulse wave velocity or central systolic BP (P = 0.99 and P = 0.54 on ANOVA, respectively). Whilst there were significant elevations from baseline for plasma [glucose] and [C‐peptide], no differences between interventions were observed. A significant increase in plasma [insulin] was observed with KNO3vs. KCl (n = 33; P = 0.014 on ANOVA) with the effect driven by the high‐dose cohort (24 mmol, n = 13; P < 0.001 on ANOVA; at T = 0.75 h mean difference 210.4 pmol/L (95% CI 28.5 to 392.3), P = 0.012). Conclusions: In healthy adults, acute physiological elevations of plasma [glucose] and [insulin] result in a lack of BP‐lowering with dietary nitrate. The increase in plasma [insulin] without a corresponding change in [C‐peptide] or [glucose] suggests that high‐dose NO3− decreases insulin clearance. A likely mechanism is via NO‐dependent inhibition of insulin‐degrading enzyme. [ABSTRACT FROM AUTHOR]

The author reflects on the organized crime against the academic peer review system of the journal. Topics discussed include meta-analysis of the effect of recombinant brain natriuretic peptide on in-hospital mortality, quality of data pooled in a published meta-analysis, and inadequacies regarding the study-design.

Background Arterial stiffness (AS), as pulse wave velocity (PWV), is a powerful independent predictor of cardiovascular events and commonly complicates type 2 diabetes (T2D). This trial aims to test if AS, measured by the VaSera machine as cardio-ankle vascular index (CAVI) and by Arteriograph measuring central PWV, can be reduced by spironolactone and/or inorganic nitrate from beetroot juice independently of blood pressure (BP) in those with or at risk of T2D. Methods A factorial design, double blind, randomised controlled trial in 18–80 year old men and women clinically diagnosed with T2D or at risk of it (body mass index (BMI) ≥ 27 kg m −2 , positive family history or glucose intolerance). The study lasts up to 36 weeks with daily intervention of either ≤50 mg spironolactone (intervention) or ≤16 mg doxazosin (control), and beetroot juice with ≤400 mg (9 mmol) inorganic nitrate (intervention) or placebo beetroot juice, 0 mg nitrate (control). Non-invasive AS measurements are carried out at baseline and then at 12-week intervals thereafter. Results To date, 95 participants have been consented and screened, 19 of these were not suitable or not willing to participate so that 73 have been randomised with 9 participants screened as eligible and awaiting randomisation. 53 participants have completed the study. Mean baseline and follow up measures of cardiac-ankle and cardiac-aortic bifurcation PWV and BP have been straightforward. Conclusion This is a proof-of-principle trial to alter AS independent of BP in a patient sample at high cardiovascular risk. Clinical trial registration information UK Clinical Research Network Portfolio Database: 25003627. [ABSTRACT FROM AUTHOR]

The article presents author's views on the medical and legal risks associated with the prescription of unlicensed vitamin D products. Topics discussed include specific requirements for vitamin D replacement in vitamin D deficiency and insufficiency, benefits of prescribing vitamin D products and vitamin D supplementation for prevention of mortality in adults.

What is the experience of a racial subaltern on becoming an employee of a postcolonial state? Latin America has undertaken widespread multicultural state reform, often in response to pressure from nation-wide social movements and transnational human rights activism. This provides us with a window into ways in which subaltern individuals negotiate their place in a historically exclusionary state with norms of whiteness, European codes, and literal and metaphoric distance from marginal populations. Previous research has emphasized the cooptation of subaltern actors by neoliberal postcolonial states, but we argue that a close reading of subaltern accounts yields important insights into their experiences of ambivalence, ambiguity, and agency. Neoliberal state restructuring entrained a parallel, and in many cases interconnected process that generated ambivalence among civil servants. We draw on interviews with state employees associated with multicultural educational reforms in Chile to document the registers through which indigenous subalterns position themselves regarding the politics of interculturalism and the costs of serving the state. [ABSTRACT FROM AUTHOR]

The discovery that dietary (inorganic) nitrate has important vascular effects came from the relatively recent realization of the 'nitrate-nitrite-nitric oxide ( NO) pathway'. Dietary nitrate has been demonstrated to have a range of beneficial vascular effects, including reducing blood pressure, inhibiting platelet aggregation, preserving or improving endothelial dysfunction, enhancing exercise performance in healthy individuals and patients with peripheral arterial disease. Pre-clinical studies with nitrate or nitrite also show the potential to protect against ischaemia-reperfusion injury and reduce arterial stiffness, inflammation and intimal thickness. However, there is a need for good evidence for hard endpoints beyond epidemiological studies. Whilst these suggest reduction in cardiovascular risk with diets high in nitrate-rich vegetables (such as a Mediterranean diet), others have suggested possible small positive and negative associations with dietary nitrate and cancer, but these remain unproven. Interactions with other nutrients, such as vitamin C, polyphenols and fatty acids may enhance or inhibit these effects. In order to provide simple guidance on nitrate intake from different vegetables, we have developed the Nitrate ' Veg- Table' with ' Nitrate Units' [each unit being 1 mmol of nitrate (62 mg)] to achieve a nitrate intake that is likely to be sufficient to derive benefit, but also to minimize the risk of potential side effects from excessive ingestion, given the current available evidence. The lack of data concerning the long term effects of dietary nitrate is a limitation, and this will need to be addressed in future trials. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor refers to articles in the issue, including pharmacology of immunomodulatory drugs, fetal ductus arteriosus constriction or closure on use of fluoxetine, and direct acting anticoagulants (DOACs).

Background: Epidemiological and animal studies suggest the potential of dietary nitrate (NO3−) to inhibit atherogenesis. Spironolactone may improve arterial stiffness. We tested if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness versus placebo/doxazosin, to control for blood pressure (BP), in a population with or at risk of type 2 diabetes [1]. Methods: A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial were randomized to nitrate-containing beetroot juice or nitrate-depleted juice, and spironolactone or doxazosin. Ultrasound for carotid diameter (CD, mm) and intima-media thickness (CIMT, mm) was performed at baseline, 3- and 6-months. Carotid stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph®) and carotid lumen area. Data was analysed by modified intention-to-treat and mixed-model effect, adjusted for confounders. Results: 93 participants had a baseline evaluation; 86% had follow-up data. No statistical interactions occurred between the juice and drug arms. BP was similar between the juices and between the drugs. CIMT was significantly lower following nitrate-containing, compared with placebo juice [−0.06 (95% Confidence Interval −0.12, −0.01), p = 0.022], with no effect on CD. CS reduction was similar between juices [−0.38(−0.67, −0.10) with placebo, −0.13 (−0.42, 0.16) with active juice] and the drugs [−0.30(−0.58, −0.02) with doxazosin, −0.21(−0.51, 0.09), with spironolactone]. No differences were detected between spironolactone or doxazosin on CIMT and CD. Conclusion: 6 months' intervention with dietary nitrate influences vascular remodelling, but not carotid stiffness or diameter. Neither spironolactone nor doxazosin had a BP-independent effect on carotid structure and function. [ABSTRACT FROM AUTHOR]

The article presents editors' report about the "British Journal of Clinical Pharmacology" for 2015. Information included in the report include the number of articles published in the journal, the themes of the journal for the year, and the journal submissions from January 1, 2015. It also includes the changes in the periodical's editorial boards.

A response from the authors of the article "Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway" in the June 2013 issue is presented.

The Chemical Weapons Convention prohibits the development, production, acquisition, stockpiling, retention, transfer or use of chemical weapons by Member States. Verification of compliance and investigations into allegations of use require accurate detection of chemical warfare agents (CWAs) and their degradation products. Detection of CWAs such as organophosphorus nerve agents in the environment relies mainly upon the analysis of soil. We now present a method for the detection of the nerve agent VX and its hydrolysis products by gas chromatography and liquid chromatography mass spectrometry of ethanol extracts of contaminated white mustard plants (Sinapis alba) which retained the compounds of interest for up to 45 days. VX is hydrolysed by the plants to ethyl methylphosphonic acid and then to methylphosphonic acid. The utility of white mustard as a nerve agent detector and remediator of nerve agent-polluted sites is discussed. The work described will help deter the employment of VX in conflict. [ABSTRACT FROM AUTHOR]