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J Gerry Coghlan,1 Christina Picken,2 Lucie H Clapp21Department of Cardiology, Royal Free Hospital, London NW3 2QG, UK; 2Institute of Cardiovascular Sciences, University College London, London WC1E 6JF, UKAbstract: Selexipag is a compound that was designed to overcome the issues associated with oral administration of prostanoid compounds, beraprost and treprostinil in the treatment of pulmonary hypertension (PAH). As a selective IP agonist, it was designed to avoid the off-target prostanoid effects especially in the gastrointestinal system. To place this compound in context, this paper briefly reviews the efficacy, tolerability, and safety of subcutaneous, inhaled, and oral prostanoid preparations and comparesthemto selexipag. Selexipag is the first agent targeting a prostanoid receptor where a reduction in the primary efficacy morbidity/mortality composite end-point has been demonstrated. While safety outcomes favor selexipag over placebo, tolerability issues remain. Efficacy in terms of improvement in effort tolerance, hemodynamic and mortality benefit is less than seen with IV therapy. This is the first prostanoid demonstrated in a clinical trial to have added benefit in those on background double combination therapy and the first non IV prostanoid to demonstrate outcome benefit in the connective tissue disease (CTD) population in a randomized controlled trial.Keywords: prostacyclin, prostaglandin, safety, tolerability, adverse events, efficacy

The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3-c]pyridine-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4). Initial [Copyright &y& Elsevier]

The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4). [Copyright &y& Elsevier]

A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4). [Copyright &y& Elsevier]

We investigated the effect of algal contact time (ACT) and horizontal water velocity (HWV) on the performance of pilot-scale Filamentous Algae Nutrient Scrubbers (FANS) treating river water during the NZ summer. The FANS floways were seeded with a mixture of four New Zealand native filamentous algal species (Oedogonium sp., Cladophora sp., Rhizoclonium sp., and Spirogyra sp.) and allowed to establish over one month. River water was pumped onto the top of each FANS at different flow rates (2, 4 or 8 L min -1 ) to give ACTs from 0.6 to 10.1 min depending on FANS length (6-24 m) and HWV from 0.04 to 0.16 m s -1 . FANS inflow and final outflows were monitored three times a week for nitrate and DRP concentrations and FANS algal biomass was harvested weekly. Average biomass productivity was significantly higher on the FANS with shorter ACT. For example, biomass productivity of the 24 m length FANS with 2.5 min ACT were 67% higher (11.2 g DW m -2 d -1 ) than that with four times the ACT (10.1 min). Irrespective of the HWV the biomass productivity declined down the length of the floways (with longer ACT) and the decline was greater at lower HWV. The decreased biomass productivity at lower HWV (and/or higher ACT) was likely attributable to the daytime carbon limitation of photosynthesis (at pH > 9.5) and heat stress with elevated daytime water temperature (at >30 °C). Despite the short ACT (<10.1 min) the single pass pilot-scale FANS effectively removed both nitrate-N and DRP from the river water, with >35% removal of both NO 3 -N (from 0.49 to <0.32 mg N L -1 ) and DRP (from 0.14 to <0.09 mg P L -1 ). Both the nitrogen and phosphorus content of the harvested algal biomass were unaffected by both HWV and ACT and typical (N: ∼2.0%; P: 0.2-0.3%) of the literature values (N: 1.5-3.0%; P: 0.15-0.32%). Compared with constructed wetland nutrient removal (0.1 g N m -2 d -1 ; 0.08 g P m -2 d -1 ), the FANS achieved up to 2.5-fold higher nitrogen removal (0.24 N m -2 d -1 ) through algal nitrogen assimilation followed by subsequent algal harvest and up to 4-fold higher phosphorus removal (0.34 g P m -2 d -1 ) through a combination of algal phosphorus assimilation and some P-precipitation under photosynthesis-mediated elevated daytime pH levels (pH > 9.0). This research indicates that FANS have the potential to require less than half the land area of constructed wetlands for the same level of nitrogen removal and that they require only a few weeks to establish to achieve full performance. Moreover, FANS have the further benefit of resource recovery for beneficial re-use of harvested algal biomass for animal feed, fertiliser, or biofuel., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

An elevated theta/beta ratio in the EEG has long been observed among individuals with Attention Deficit Hyperactivity Disorder (ADHD). The theta/beta ratio was previously hypothesised to be an index of arousal, but a number of studies failed to find any association between the ratio and indices of arousal, instead proposing that the theta/beta ratio may actually be indicative of cognitive processing. This hypothesis was tested by Clarke et al using a sample of healthy adults, with results indicating that the theta/beta ratio correlated with a marker of cognitive processing (P300 latency in an auditory oddball task), while P300 amplitude correlated with an arousal marker (alpha power). The aim of this study was to test whether similar results could be found in a sample of 41 adults with the combined type of ADHD. EEGs were recorded during an eyes-closed resting condition and an auditory oddball task. Results demonstrated that the theta/beta ratio correlated significantly with P300 latency. Absolute alpha power did not correlate significantly with P300 amplitude or P300 latency. These results support the hypotheses that the theta/beta ratio is a marker of cognitive processing capacity in both the general population and in participants with ADHD, and that the alpha/arousal linkage is anomalous in ADHD.

Prostacyclin mimetics (PMs) are effective for the treatment of pulmonary arterial hypertension (PAH). However, their clinical use may be limited by their adverse events. This study aims to quantify the different PM adverse events (AEs) with regard to their selectivity towards the prostacyclin (IP) receptor and their administrative routes. The study included randomised, placebo-controlled trials comparing iloprost, beraprost, treprostinil, and selexipag to placebo (published 2002–2016). We report the group efficacy differences between treatment and placebo by weighted and standardised mean difference. The probability of adverse events was determined by the odds ratio (OR). Of the 14 randomised clinical trials involving 3518 PAH patients, outcome and adverse event data were meta-analysed by drug type and route of administration. Prostacyclin mimetics comparison demonstrated a more significant discontinuation of the IP-selective agonist, selexipag, due to an adverse event (OR = 2.2; 95% CI: 1.5, 3.3). Compared to placebo, site pain associated with subcutaneously administered treprostinil was the most significant likely adverse event (OR = 17.5; 95% CI: 11.1, 27.1). Parenteral PMs were associated with fewer adverse effects overall. The overall efficacy of PMs to improve 6-minute walk distance by 16.3 meters was significant (95% CI: 13.0, 19.7). Decreases in pulmonary vascular resistance index (SMD = -5.5; 95% CI: -10.1, -0.9; I ² = 98%) and mean pulmonary arterial pressure (SMD = -1.0; 95% CI: -2.6, -0.7; I ² = 99%) in treatment groups were found to be significant. Adverse event profiles varied in response to administration route and PM type but were not negated by use of a selective IP agonist. Prostacyclin mimetics exposure to non-target IP receptors may underpin some AEs reported., Competing Interests: C.P. is funded by a BBSRC Case PhD Studentship project which is partially funded by Lung Biotechnology, USA. Clapp has acted as a consultant and received research grants from United Therapeutics and Lung Biotechnology, USA. G.C. has received research grants from Actelion LTD (Johnson & Johnson), and honoraria and consultancy fees from Actelion; United Therapeutics; GSK; Pfizer & Bayer. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results

Quality of life is multifactorial, but may not be adequately assessed using existing validated health measures. The Mother-Generated Index, a subjective tool to measure postnatal quality of life, was assessed in a study of 102 women in Tayside, Scotland. They specified the most important areas of their lives having had a baby, and scored these. The Index showed good correlation with established measures of physical and psychological wellbeing, and accurately tracked attitudes towards the baby and the partner. Face, criterion and construct validity were all demonstrated. As both content and scoring are subjectively determined, the Index encourages a holistic assessment.

The synthesis of a novel series of guanine analogues is reported. The compounds have been assessed in vitro and some analogues have been found to be inhibitors of phosphodiesterase type 7 (PDE7).

Background: The role of planned neck dissection after organ preservation therapy with radiotherapy or chemotherapy/radiotherapy for advanced head and neck cancers presenting with clinically positive neck disease is still being elucidated. The aim of this study is to review the outcomes of such patients treated by organ preservation therapy at our institution., Methods: A retrospective chart review of 33 patients who underwent planned neck dissections after organ preservation therapy for advanced primary head and neck malignancy. Endpoints measured were disease-free survival and local, regional, and distant control., Setting: Tertiary metropolitan medical center., Results: Two-year actuarial disease-free survival was 61%, and neck control was 92%, with only two failures in the neck. The use of neoadjuvant chemotherapy and total dose of radiotherapy did not correlate with neck control or disease-free survival. The presence of pathologically positive nodal disease at the time of neck dissection did not correlate with recurrent neck disease, but was a predictor of local recurrence (p = .0086)., Conclusions: Our data suggest that for patients undergoing planned neck dissection after organ preservation therapy, neck control is obtained in almost all cases. The presence of pathologically positive nodal disease at the time of surgery may have implications for the incidence of local recurrence.

The synthesis and pharmacological profile of a novel series of 7-methoxybenzofuran-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).

Ectopic thyroid is rare and occasionally presents suddenly in childhood. Adult patients with thyroid ectopy who develop local symptoms commonly have an enlarged ectopic gland and hypothyroidism. We describe the first case of an adult patient who sudden presented with sudden dysphagia and dyspnea caused by a large lingual thyroid in clinical and biochemical euthyroidism. Treatment consisted of surgical removal of the ectopic gland and thyroid hormone replacement therapy.

Objective: To report the complication rate from planned, posttreatment neck dissections in patients who show control of primary squamous cell carcinoma by chemotherapy and radiotherapy or radiotherapy alone., Design: Retrospective review of case series., Setting: Georgetown University Medical Center, Washington, DC., Patients: Thirty-four patients with clinically positive neck disease treated with organ preservation therapy for squamous cell carcinoma of the head and neck., Interventions: Planned neck dissection after treatment with chemotherapy and radiotherapy or radiotherapy alone., Main Outcome Measure: Perioperative complications., Results: Forty-one neck dissections were performed on 34 patients. Complications were seen in 13 (38%) of 34 patients and 15 (37%) of 41 neck dissections. Wound complications occurred in 9 (22%) of 41 dissections. Neck dissection complication rate did not correlate with previous use of chemotherapy or with the use of brachytherapy at the primary site at the time of the neck dissection. Preoperative radiotherapy dose greater than 70 Gy was associated with complications in 58% vs 29% when preoperative dose was less than 70 Gy (P = .09). This trend was reflected primarily in wound complications (42% vs 14%; P = . 10) and reached significance for skin flap necrosis (33% vs 0%; P = .005). Other factors that were associated with increased complications were preoperative albumin level less than 38 g/L and early neck drain removal., Conclusions: The complication rate associated with planned posttreatment neck dissection is similar to that previously reported for neck dissection. Wound complications are more common when higher preoperative radiotherapy doses are used.

Although the use of carotid artery stents is increasing, the management of recurrent stenosis after their placement is undefined. The authors report on a patient who underwent two left carotid endarterectomies followed by left carotid angioplasty and stent placement for recurrent stenosis. A third symptomatic recurrence was subsequently managed by placement of a saphenous vein interposition graft from the common carotid artery to the distal cervical internal carotid artery. The patient remained without hemispheric or retinal ischemia at his 5-month follow-up visit. Interposition grafting should be considered as a treatment option for carotid restenosis after initial endarterectomy and stent placement.

1. The relative binding affinity of zearalenone, alpha-zearalenol, and beta-zearalenol for estrogen receptors was determined in the pig, rat and chicken. 2. Similar relative binding patterns were observed, with alpha-zearalenol exhibiting greater affinity than zearalenone and beta-zearalenol the least binding affinity in all species. 3. The relative binding affinity of alpha-zearalenol was greater in pig, than in rat and significantly greater than in chicken. 4. Interspecies differences in zearalenone sensitivity may be due to the binding affinity of alpha-zearalenol for estrogen receptors and differences in zearalenone metabolites formed.

Closed mitral commissurotomy (CMC) was performed at the National Heart Institute in 303 patients (73% women, 27% men; mean age 40 years) with acquired isolated mitral stenosis between 1954 and 1980. The average mean mitral valve gradient decreased from 14.2 +/- 0.4 to 5.3 +/- 0.4 mm Hg (p less than 0.001), and mitral valve area index increased from 0.7 +/- 0.03 to 1.4 +/- 0.9 cm2/m2 (p less than 0.001). The perioperative mortality was 2%. Ninety-two percent of patients improved one or more functional classes after CMC. Actuarial survival was 95%, 82% and 70% at 5, 10 and 15 years after CMC, respectively. Fifty-four patients (18%) required mitral valve replacement (MVR) a mean of 9.6 years after commissurotomy (range 1-26 years). Before CMC, factors associated with later MVR included preoperative functional class, calcification of the mitral valve, and the absence of an opening snap. After CMC, poor functional improvement, congestive heart failure, atrial fibrillation, and the necessity for a repeat CMC were associated with late MVR. Catheterization after CMC showed that patients who later required MVR had a smaller decrease in left atrial pressure (p less than 0.001), more mitral regurgitation (p less than 0.001), and were more likely to have pulmonary hypertension (p less than 0.05). The indications for MVR were residual stenosis with or without mild mitral regurgitation in 33 patients (61%), restenosis in 15 (28%), and moderate-to-severe regurgitation in six (11%). Perioperative mortality for valve replacement was 13%. Among survivors, 88% improved at least one functional class after valve replacement. Actuarial survival was estimated to be 95% at 5 years and 74% at 10 years after MVR. This study confirms that CMC provides excellent long-term hemodynamic and clinical improvement in appropriately selected patients. When symptomatic deterioration occurs late after CMC, MVR restores clinical and hemodynamic improvement in many patients. CMC continues to be performed at the National Heart Institute in selected patients with acquired mitral stenosis.