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In recent years, there has been a substantial increase in the development of antitussive therapies and the first new therapy, gefapixant has been licenced in Europe. This review describes current unlicenced treatments for chronic cough and details treatments currently in development for refractory chronic cough and cough in idiopathic pulmonary fibrosis, as well as compounds previously explored. [ABSTRACT FROM AUTHOR]

Introduction: The PAGANINI study evaluated the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough (RCC). Methods: PAGANINI was a randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose-finding, phase 2b study. Adults with RCC lasting ≥ 12 months and cough severity ≥ 40 mm on a visual analog scale at screening were enrolled. Participants were randomized 1:1:1:1 to twice-daily 25 mg, 75 mg, or 150 mg oral eliapixant or placebo for 12 weeks. The primary endpoint was change from baseline in 24-h cough count after 12 weeks of intervention. Results: Overall, 310 participants were randomized to twice-daily eliapixant 25 mg (n = 75), 75 mg (n = 78), 150 mg (n = 80), or placebo (n = 77). A statistically significant dose–response signal with eliapixant was detected for the primary endpoint (all dose–response models, adjusted p < 0.1; one-sided). Adverse events (AEs) were reported in 39 (51%) participants with placebo and 43–51 (57–65%) participants receiving eliapixant. The most common AE was dysgeusia, occurring in 1% (n = 1) of the placebo group and 1–16% (n = 1–13) of the eliapixant groups in a dose-related manner. One case of a moderate drug-induced liver injury occurred in a participant receiving 150 mg twice-daily eliapixant. Conclusion: Eliapixant demonstrated efficacy and a favorable taste tolerability profile in RCC. However, a drug-induced liver injury contributed to intensified liver monitoring in clinical trials with eliapixant and discontinuation of the entire development program in all indications by Bayer AG. Trial Registration: ClinicalTrials.gov identifier NCT04562155; registered September 18, 2020. [ABSTRACT FROM AUTHOR]

Introduction: To determine the optimal dose of sivopixant, a highly selective P2X3 receptor antagonist, for refractory or unexplained chronic cough (RCC/UCC). Methods: In this phase 2b, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial, patients received sivopixant 50, 150, or 300 mg or placebo once daily for 4 weeks. The primary endpoint was a change from baseline in 24-h cough frequency (coughs/h) with sivopixant vs placebo. Results: Overall, 390/406 randomized patients completed the study. Placebo-adjusted changes in hourly cough count over 24 h were 13.17% (P = 0.3532), − 1.77% (P = 0.8935), and − 12.47% (P = 0.3241) and in cough severity (visual analog scale) were 1.75 mm (P = 0.5854), − 1.21 mm (P = 0.7056), and − 6.55 mm (P = 0.0433) with sivopixant 50, 150, and 300 mg, respectively. Placebo-adjusted changes from baseline in Leicester Cough Questionnaire total scores were − 0.37 (P = 0.4207), − 0.07 (P = 0.8806), and 0.69 (P = 0.1473) with sivopixant 50, 150, and 300 mg, respectively. Additionally, 61.3%, 78.3%, 86.8%, and 71.4% of patients receiving sivopixant 50, 150, and 300 mg and placebo, respectively, reported any improvements in Patient Global Impression of Change. The incidence of treatment-emergent adverse events (TEAEs) was 25.7%, 32.0%, 49.0%, and 20.6% in sivopixant 50, 150, and 300 mg and placebo groups, respectively; all TEAEs in the sivopixant group were mild-to-moderate. Conclusion: Sivopixant did not demonstrate a statistically significant difference vs placebo in change from baseline in 24-h cough frequency. The dose of 300 mg has potential for RCC/UCC, showing the greatest improvements in cough frequency and patient-reported outcomes and dose-related mild to moderate reversible taste disturbance, although further trials are needed. Clinical Trial Registration: ClinicalTrials.gov identifier NCT04110054; registered September 26, 2019. [ABSTRACT FROM AUTHOR]

Purpose: Objective cough frequency is used to assess efficacy of chronic cough (CC) treatments. The objective of this study was to explore the relationship between objective cough frequency and cough-specific patient-reported outcomes (PROs) and estimate a clinically meaningful change threshold (MCT) for objective cough frequency. Methods: Data collected in a phase 2b study in participants with refractory or unexplained CC were used to investigate the relationship between 24-h cough frequency (measured using an ambulatory cough monitor) and cough-specific PROs (i.e., cough severity visual analog scale, cough severity diary, Leicester Cough Questionnaire). Convergent validity was assessed using Spearman ρ. An MCT for 24-h cough frequency was estimated using the patient global impression of change (PGIC) scale as an anchor. Results: Correlations between 24-h cough frequency and cough-specific PROs at baseline, Week 4, and Week 12 were significant (P < 0.0001) but low to moderate in strength (ρ = 0.30–0.58). Participants categorized as very much improved/much improved (i.e., PGIC of 1 or 2) or minimally improved (i.e., PGIC of 3) had mean 24-h cough frequency reductions of 55% and 30%, respectively. Receiver operating characteristic curve analysis suggested that a 24-h cough frequency reduction of 38% optimizes sensitivity and specificity for predicting a PGIC score of 1–3. Conclusion: Objective 24-h cough frequency is significantly associated with cough-specific PROs, but cough frequency and PROs most likely capture distinct aspects of CC. A ≥ 30% reduction in 24-h cough frequency is a reasonable MCT to define treatment response in CC clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Available therapies for acute cough, a condition frequently caused by a viral upper respiratory tract infection (URTI), have shown limited evidence of efficacy. Gefapixant, a P2X3-receptor antagonist, has demonstrated efficacy and safety in studies of the treatment of refractory or unexplained chronic cough, but its efficacy for treating acute cough has not been previously studied. Methods: This was a phase 2a, randomized, double-blind, placebo-controlled, parallel-group, pilot study. Healthy volunteers were randomized 1:1 to receive twice-daily gefapixant 45 mg or placebo and inoculated with human rhinovirus 16 to induce URTI and cough. Participants were observed while quarantined for 7 days after the start of treatment. The primary endpoint was awake cough frequency on day 3, which was objectively measured with a cough-recording device. Secondary endpoints included change from baseline to day 3 in subjective cough severity measures (cough severity visual analog scale, Cough Severity Diary) and cough-specific quality of life (Leicester Cough Questionnaire–acute). Results: Of the 46 participants who met inclusion criteria [mean (standard deviation, SD) age, 24.6 (6.5) years; females, n = 8], 40 completed the study (gefapixant, n = 21; placebo, n = 19). There was no significant difference in awake cough frequency on day 3 between the gefapixant and placebo groups [least squares means, 2.4 versus 2.7 coughs per hour, respectively; mean difference (95% confidence interval, CI), −0.3 (−2.3, 1.7); P = 0.75]. There were no significant between-group differences for any of the secondary endpoints. Peak cough frequency was low and occurred later in the study than expected (days 4–5). The safety profile was consistent with that of previous studies of gefapixant. Conclusion: Compared with placebo, gefapixant did not reduce the frequency or severity of acute cough secondary to induced URTI. Induced viral URTI produced mild symptoms, including lower cough frequency than observed in previous studies of patients selected for acute cough associated with naturally occurring URTI. Trial Registration: ClinicalTrials.gov, NCT03569033; EudraCT, 2017-000472-28; protocol number, MK-7264-013. [ABSTRACT FROM AUTHOR]

Introduction: In phase 3 trials (COUGH-1/COUGH-2), gefapixant 45 mg twice daily significantly reduced 24-h cough frequency vs placebo in refractory or unexplained chronic cough (RCC or UCC). Methods: Here, the efficacy of gefapixant 45 mg vs placebo was evaluated across COUGH-1/COUGH-2 in predefined subgroups based on sex, region, age, cough duration, cough severity, cough frequency, and diagnosis (RCC, UCC). Awake cough frequency reductions at Week 12 and LCQ response rates (i.e., ≥ 1.3-point improvement) at Week 24 were assessed. Results: Among 1360 participants analyzed, gefapixant 45 mg resulted in consistent awake cough frequency reductions overall and across predefined subgroups at Week 12. Gefapixant also resulted in improved LCQ scores across subgroups at Week 24; ≥ 70% of participants in each subgroup treated with gefapixant 45 mg had an LCQ response. Conclusion: These data suggest gefapixant 45 mg provides consistent objective and subjective efficacy across subgroups of individuals with RCC or UCC. [ABSTRACT FROM AUTHOR]

Background and Objective: There is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers. Methods: We conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant. Results: Peak plasma concentrations of eliapixant were reached 3–4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak–trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events. Conclusions: Eliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough. Clinical Trial Registration: Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017). Plain Language Summary: There are few effective treatments for patients with a long-term (chronic) cough. It is thought that chronic cough is caused by nerves becoming oversensitive, wrongly causing a cough when there is no need. We tested a new drug called eliapixant in 47 healthy men. Eliapixant reduces the excessive nerve signaling responsible for chronic cough. We looked for side effects of eliapixant and measured how it behaves in the body. In particular we looked for side effects relating to the sense of taste because gefapixant, a similar drug to eliapixant, can affect taste. Participants took one of four eliapixant doses or a placebo twice daily for 2 weeks. The highest levels of eliapixant in the blood were seen 3–4 h after taking the drug, and stable concentrations were seen after about 6 days. At the two highest doses, eliapixant reached concentrations in the body that should be high enough to work in patients with chronic cough. Side effects were generally similar between eliapixant and placebo. Taste-related side effects were mild and went away without needing treatment. The positive results of this study meant that eliapixant could be tested in patients with chronic cough. [ABSTRACT FROM AUTHOR]

Introduction: Chronic cough is a highly problematic symptom for patients with idiopathic pulmonary fibrosis (IPF); limited therapeutic options are available. We evaluated gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough in IPF. Methods: This randomized, double-blind, placebo-controlled, crossover study included subjects with IPF. Sequence A included gefapixant 50 mg BID (period 1; 14 days) followed by placebo (period 2; 14 days); sequence B had the opposite sequence of treatments. This regimen was specified in a protocol amendment that modified the original active treatment regimen of gefapixant 50 mg BID for 10 days and 150 mg BID for 4 days. Patients randomized to the original treatment regimen were excluded from efficacy analyses but included in safety assessments. The primary efficacy endpoint was change from baseline in awake cough frequency (coughs/hour) from periods 1 and 2 combined. Adverse events (AEs) were monitored throughout the study. Results: A total of 51 subjects were randomized, 44 of whom were randomized to treatment sequences evaluated in the primary efficacy analysis (i.e., 22 subjects in sequence A and 22 subjects in sequence B); seven subjects received the treatment assigned before the protocol amendment and were excluded from efficacy analyses. The change from baseline in awake cough frequency from periods 1 and 2 combined (mixed model for repeated measures analysis) did not demonstrate a significant reduction versus placebo in cough at day 14 (p = 0.90); in a post hoc analysis of log-transformed data p value for reduction versus placebo at day 14 was 0.07. The most common AEs were related to taste (dysgeusia and ageusia). Conclusions: Gefapixant was generally well tolerated but was not associated with a significant improvement in chronic cough in subjects with IPF as defined by the primary endpoint in this study. Trial Registration: NCT02502097. [ABSTRACT FROM AUTHOR]

Small to medium irrigation ponds provide substantial quantities of water for irrigation in the Mid-Atlantic region of the U.S. The concentrations of the fecal indicator organism Escherichia coli (E. coli) are used to evaluate the microbial water quality of irrigation sources. Little is known about the spatiotemporal variability of E. coli concentrations in pond water and the possible effects on monitoring and management of the microbial quality of irrigation water from these ponds. The objective of this work was to test the hypotheses that (a) spatial patterns of E. coli concentrations exist that are preserved both intra- and interannually, and (b) persistent spatial patterns in water quality parameters exist and correlate with persistent patterns of E. coli concentrations. Sampling was conducted fortnightly during the summer months in 2016 to 2018 and consisted of taking water quality measurements at 23 and 34 locations in ponds P1 and P2, respectively. Interannual variability of E. coli was observed in both ponds as was substantial spatial variability of E. coli concentrations within each year. The mean relative difference (MRD) analysis was used to identify temporally stable patterns of E. coli concentrations within the ponds. These patterns found for individual years showed significant positive correlations with each other and with the overall pattern derived from the 3-year dataset. Correlation coefficients of patterns varied from 0.487 to 0.842 in P1 and from 0.467 to 0.789 in P2 (p < 0.05). MRD patterns of water quality parameters and of E. coli concentrations were also significantly correlated. Within the 3-year dataset, the highest positive correlations were observed for chlorophyll-a and turbidity while the dissolved oxygen concentrations demonstrated the greatest negative correlations. Results of the present study emphasize the advisability and feasibility of finding temporally stable spatial patterns in microbial water quality within irrigation ponds. [ABSTRACT FROM AUTHOR]

Purpose: This analysis assesses clinical characteristics of patients with refractory chronic cough (RCC) or unexplained chronic cough (UCC) enrolled in a phase 2 study to better understand this patient population. Methods: Patients with RCC/UCC lasting for ≥ 1 year and cough severity visual analog scale (VAS) score of > 40 mm at screening were eligible. Demographics, clinical characteristics, and medical history were collected at baseline. Cough-related measures included cough severity VAS, Cough Severity Diary (CSD), Leicester Cough Questionnaire (LCQ), and a structured cough-trigger questionnaire. Medication history included all medications 30 days before screening and chronic cough treatments within 1 year before screening. Data were summarized using descriptive statistics. Results: Patients (N = 253; female, 76%; mean age, 60 years) had severe (mean cough severity VAS, 57.5 mm) and long-lasting (median duration, 11 years) cough. The most burdensome self-reported aspects included psychological and social factors (LCQ) and cough frequency and intensity (CSD). Patient-reported triggers were consistent with cough hypersensitivity (e.g., 95% to 96% reported irritation or tickle in throat). Common reported comorbidities included gastroesophageal reflux disease (GERD; 56%), allergic rhinitis (47%), and asthma (30%); 12% of patients had been diagnosed with all 3 conditions. The most common prior medications included inhaled or oral steroids (21%), antihistamines (15%), and antacids (15%). Conclusion: Patients with RCC/UCC had severe, long-lasting, and burdensome cough with clinical features of cough hypersensitivity. Many patients had been diagnosed with GERD, allergic rhinitis, and asthma but had a persistent cough despite treatment of these conditions. Trial registration: ClinicalTrials.gov, NCT02612610; registered November 20, 2015 [ABSTRACT FROM AUTHOR]

The constituents of many traditional Chinese herbal remedies are currently at the forefront of modern cancer research. Baicalein, a bioactive flavone widely used in nutraceuticals and pharmaceuticals, has shown great potential in the treatment and prevention of cancer without causing severe side effects. Baicalein induces cancer cell apoptosis and causes cell cycle arrest. It shows inhibitory effects on angiogenesis, metastasis, and inflammation, all of which are necessary for the promotion and progression of cancer. This review presents an overview of the anticancer effects and mechanisms of baicalein. In addition, the bioavailability of baicalein and approaches to improve it are summarized. Moreover, treatments of baicalein in combination with other anticancer agents are also mentioned. [ABSTRACT FROM AUTHOR]

Cough is currently the most common reason for patients to visit a primary care physician in the UK, yet it remains an unmet medical need. Current therapies have limited efficacy or have potentially dangerous side effects. Under normal circumstances, cough is a protective reflex to clear the lungs of harmful particles; however, in disease, cough can become excessive, dramatically impacting patients' lives. In many cases, this condition is linked to inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD), but can also be refractory to treatment and idiopathic in nature. Therefore, there is an urgent need to develop therapies, and targeting the sensory afferent arm of the reflex which initiates the cough reflex may uncover novel therapeutic targets. The cough reflex is initiated following activation of ion channels present on vagal sensory afferents. These ion channels include the transient receptor potential (TRP) family of cation-selective ion channels which act as cellular sensors and respond to changes in the external environment. Many direct activators of TRP channels, including arachidonic acid derivatives, a lowered airway pH, changes in temperature, and altered airway osmolarity are present in the diseased airway where responses to challenge agents which activate airway sensory nerve activity are known to be enhanced. Furthermore, the expression of some TRP channels is increased in airway disease. Together, this makes them promising targets for the treatment of chronic cough. This review will cover the current understanding of the role of the TRP family of ion channels in the activation of airway sensory nerves and cough, focusing on four members, transient receptor potential vanilloid (TRPV) 1, transient receptor potential ankyrin (TRPA) 1, TRPV4, and transient receptor potential melastatin (TRPM) 8 as these represent the channels where most information has been gathered with relevance to the airways. We will describe recent data and highlight the possible therapeutic utility of specific TRP channel antagonists as antitussives in the clinic. [ABSTRACT FROM AUTHOR]

Along with upper airway cough syndrome (formerly, postnasal drip syndrome) and eosinophilic airway inflammation (asthma, nonasthmatic eosinophilic bronchitis), gastroesophageal reflux disease (GERD) is generally considered among the most common etiologies of chronic cough. Indeed, cough management guidelines published by numerous respiratory societies worldwide recommend evaluation and treatment of GERD as an integral component of the diagnostic/therapeutic algorithm for the management of chronic cough. However, a significant number of patients with chronic cough presumed due to GERD do not report improvement despite aggressive acid-suppressive therapy. Some of these refractory cases may be due to the recently appreciated entity of nonacid or weakly acidic reflux. Further contributing to the controversy are recent studies that demonstrate that patients with chronic cough do not have excessive reflux events relative to healthy volunteers. Although a temporal relationship between cough and reflux events has been suggested by studies utilizing impedance-pH monitoring of reflux events and objective cough recording, consensus is lacking in terms of whether this temporal relationship proves a causal link between reflux and cough. The fourth American Cough Conference (New York, June 2013) provided an ideal forum for the debate of this issue between two internationally recognized experts in the field of reflux and chronic cough. [ABSTRACT FROM AUTHOR]

Traditionally push-button and symptom diaries have been used to document cough events, especially when examining temporal associations between cough and reflux events. More recently, acoustic devices have allowed more accurate recording of cough events, and compared with the latter traditional techniques reported 6-18 times more coughing. Whether the differences reported between these techniques represents disparities in subject groups or cough detection and quantification methods is unknown. In this issue of the American Journal of Gastroenterology, Kavitt et al. show that listeners of such recordings have a 4-fold increase in odds of recording cough events compared with patients using push-button techniques, and that even when using a 5-min window to assess temporal concordance/discordance, over 70% of coughs were not reported by the patients. These observations have potential significant implications when assessing temporal associations between cough and reflux, and thus any clinical decision making based on these data. This editorial examines both the findings of Kavitt et al. and discusses the pitfalls and benefits of validated accurate documentation of cough. [ABSTRACT FROM AUTHOR]

Background: A respiratory distress symptom cluster has recently been identified in lung cancer associated with breathlessness, cough and fatigue, and the study reported here is part of a wider body of work being undertaken to develop a novel non-pharmacological intervention (NPI) for the management of this symptom cluster. The current paper reports the views of health care professionals (HCPs) involved with cancer care regarding the most appropriate ways of developing and delivering such a novel intervention. Methods: Five focus groups, supplemented with additional telephone interviews, were conducted with a range of both community- and acute-based HCPs involved in symptom management for lung cancer patients. Participants included oncologists, palliative care consultants, specialist nurses, occupational therapists and physiotherapists. The focus groups were transcribed verbatim and analysed using NVIVO to support a framework analysis approach. Results: The current delivery of NPIs was found to be ad hoc and varied between sites both in terms of what was delivered and by which health care professionals. The provision of NPIs within acute medical settings faced common problems concerning staffing time and space, and there was a recognition that the preference of most patients to make as few hospital visits as possible also complicated NPI teaching. Moreover, there may only be a small window of opportunity in which to effectively teach lung cancer patients a novel NPI as the period between diagnosis and the onset of severe symptoms is often short. Discussion: The participants agreed that the novel symptom management NPI should be individually personalised to the needs of each patient and be available for patients when they become receptive to it. Moreover, they agreed that the intervention would be most effective if delivered to patients individually rather than in groups, outside acute medical settings where possible and closer to patient's homes, should be delivered by an HCP rather than a trained volunteer or lay person and should involve informal carers wherever practicable. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to explore the patient experience of cough in a population of patients with lung cancer.Methods: A qualitative exploratory study design was developed and elicited the views of 26 patients with lung cancer who had current or past experience with cough.Results: The data's four themes highlight the complex and distressing nature of cough, including its interaction with other symptoms, such as breathlessness, fatigue and sleep disturbance. A theme around descriptions of cough suggests typically a dry tickly cough and highlights mechanical and environmental triggers for cough. The theme around the effects of cough in daily life shows the impact of cough in socialising, the embarrassment from cough and the psychological effects experienced by patients. The last theme focuses on strategies for coping with and managing cough, showing the perceived ineffectiveness of current antitussives and the patients' use of a variety of approaches on an ad hoc basis to try to manage their cough often unsuccessfully.Conclusion: Cough has not received the same attention as other cancer symptoms, which means that patients' experience of a distressing and difficult symptom is often unnoticed by health care professionals. More clinical and research attention in this debilitating symptom is necessary. [ABSTRACT FROM AUTHOR]

Chronic cough is a common problem resulting in significant impairment of quality of life. Along with cough variant asthma and nasal disease, gastroesophageal reflux is considered one of three main causes of cough. Despite this, acid suppression therapy is often far from effective. This review aims to explore whether reflux can lead to cough, the circumstances in which this is most likely to occur, and the potential mechanisms linking these processes. Particular mechanisms to be explored include laryngopharyngeal reflux, microaspiration, and neuronal cross-organ sensitization. Finally, diagnostic approaches are considered. [ABSTRACT FROM AUTHOR]

Gastro-oesophageal reflux disease (GORD) is generally considered one of the three main causes of chronic cough, along with asthma and nasal disease. The diagnosis of GORD is often based upon a successful trial of anti-acid treatment however GORD is a complex condition taking many forms. Only recently have studies started to address the different types of GORD in patients with chronic cough and how these may infer the mechanisms linking these common conditions. GORD can be assessed in a number of ways; whilst endoscopy provides evidence of oesophagitis (i.e. erosive disease), 24-h ambulatory oesophageal pH monitoring may demonstrate abnormal oesophageal acid exposure in the absence of oesophageal damage (i.e. non-erosive disease). The development of oesophageal impedance monitoring now allows the assessment of all reflux events (regardless of degree of acidity) and further classification of reflux by the proximal extension e.g. to upper oesophagus or even pharynx. Chronic cough patients may still be considered to have GORD if there is a significant temporal association between reflux events and coughing. Recent studies have examined the relationships between cough and reflux events, the roles of distal and proximal/pharyngeal reflux and also micro-aspiration in chronic cough patients. Increasing evidence suggests a significant proportion of patients display statistical associations between reflux and cough events, in the absence of an excessive numbers of reflux events either within or outside of the oesophagus. [ABSTRACT FROM AUTHOR]

Currently, opiates are widely used as antitussives but have substantial side effects. Recently, it has been proposed that NOP1 receptor agonists may be useful as a novel approach to cough suppression. Therefore, we compared the effect of NOP1 receptor agonist SCH486757 with matched placebo and codeine in a multicentre, double-blind, parallel-group study in patients with subacute cough. The primary outcome was change in cough severity scores, with the key secondary outcome change in objective daytime cough counts. We studied 91 subjects with subacute cough [59 (65%) female, median age = 41 (range = 18–64) years, and median cough duration = 33 (range = 16–99) days]. Subjects were randomised to receive either SCH486757 100 mg, codeine 30 mg, or matched placebo twice daily for 5 days. Cough severity was scored throughout using a diary card and objective cough frequency recorded for 8 h at baseline and on the first and last treatment days. There were no significant differences in changes in average cough severity scores from baseline to treatment between SCH486757 and placebo [mean change = −0.57 (−30.1%) vs. mean change = −0.49 (−19.7%); P = 0.56] or between codeine and placebo [mean change = −0.72 (−33.2%); P = 0.07 compared to placebo). Changes in objective cough counts also showed no differences between the three treatment groups. There were some hints of possible limited antitussive efficacy with SCH486757. Unfortunately, the maximum clinical dose is limited by its tendency to produce somnolence. If the therapeutic ratio of NOP1 agonists could be improved, these drugs may still prove to contain effective antitussives. [ABSTRACT FROM AUTHOR]

Many factors contribute to the success of a socially parasitic strategy, especially the ability of the parasite to invade a host colony. However, little research has focused on the choices that may be made by an invading parasite, specifically whether parasites actively discriminate between different host colonies and if they have a preference for colonies of a particular size. When an allodapine social parasite, Inquilina schwarzi, was presented with colonies of their host species, Exoneura robusta, the parasites were found to invade the larger host colonies. However, it could not be ascertained from this study whether the parasites were making an active decision concerning which colony to invade, or whether they were simply more attracted to the larger colonies due to potentially stronger odour cues. Regardless of the cause, the larger host colonies are more at risk of being invaded by a social parasite, which would give parasites greater resources for exploitation and could also provide selection against the large host colony sizes. [ABSTRACT FROM AUTHOR]

variety of different methods are available for measuring cough. In clinical practice and most clinical trials subjective reporting of cough is relied upon, using scoring systems or visual analog scores (VAS). Although these measures give an indication of patients' perceptions of the severity of the symptom, they may be unreliable because they are influenced by other factors such as mood, vigilance, and expectations. An objective measure of cough would therefore be a valuable tool. In the last decade advances in computer technology and the availability of portable digital sound recording devices have resulted in a resurgence of interest in developing ambulatory systems for recording cough. The ultimate goal is an automated detection system of use in the wide variety of conditions that cause cough. Multidisciplinary teams of researchers around the world are applying techniques such as neural networks, voice recognition models, and other signal processing techniques to this problem. The main challenge is achieving high sensitivity with good discrimination of noncough signals. For cough sound detection, this is confounded by both the variability of the acoustics of cough sounds within and between individuals and the amount and variety of speech sounds that must be discriminated. Significant progress is being made and it is likely that accurate automated objective monitoring systems will be available in the near future. These systems have the potential to change the way cough is measured in clinical practice and clinical trials, allowing a better understanding of the effect of existing and novel treatments on this troublesome symptom. [ABSTRACT FROM AUTHOR]

Social parasitism has evolved at least ten times in the allodapine bees but studies that explore the parasite’s integration and exploitation of host colonies are lacking. Using colony content and dissection data, we examine how Inquilina schwarzi affects the social organisation of its host Exoneura robusta. Our samples include three critical periods in the host life cycle: initial formation of dominance hierarchies in late autumn, commencement of oviposition by host queens in late winter, and development of secondary reproductives in late spring. I. schwarzi preferentially parasitises larger host colonies in autumn, but during autumn and winter, the parasite appears to be socially invisible, living in the nest without disrupting the normal functioning of these colonies. Inquilines begin egg laying much later than their hosts, and by late spring, they have disrupted host reproductive hierarchies, leading to lower skew in ovarian sizes of their host nestmates. Living invisibly within the host nest for the first 6 months and waiting until well after host reproduction has begun before disrupting their social organisation appear to be unique among social insects. Such a change in strategy may be facilitated by the different social systems found in allodapine bees, with the social parasites possibly disrupting the reproductive hierarchies during spring to prevent or reduce the normal dispersal of some host females from their natal nests. [ABSTRACT FROM AUTHOR]

Fecal indicator bacteria (FIB) inhabiting stream sediments have become a concern with regard to recreational and irrigation water quality. Sediments contain higher concentrations of E. coli and other FIB than the overlying water column. The objective of this work was to evaluate the effect of temperature oscillations on the populations of both E. coli and enterococci in sediments and the water column. The study was conducted in a microcosm system with flow-through chambers representing a small stream with two different sediment textures. Bovine manure was freshly collected and mixed with both clayey and sandy sediment. Temperatures within the chambers oscillated from 17° to 28 °C which is representative of a diurnal summer temperature range for Maryland; the control chambers were kept at 22 °C. The effect of temperature oscillations differed depending on the sediment texture. Bacterial populations in the sandy sediment immediately increased before net die-off began. Conversely, in the chambers with the clayey sediments, there was no immediate increase in concentrations in the oscillation chambers as compared to the controls. There were significantly higher populations of both E. coli and enterococci within the oscillation sandy texture chambers compared to the control constant temperature chambers; that was not the case in the clayey sediment chambers. The die-off rates in the sandy sediments were greater than those in the clayey sediments; in the latter, bacteria populations remained almost constant throughout the experiment. Temperature oscillations should be simulated in experiments designed to estimate and compare inactivation rates for fecal indicator bacteria in sediments for future inferences on microbial water quality. [ABSTRACT FROM AUTHOR]

Environmental reservoirs of fecal indicator bacteria (FIB) are attracting increasing attention because of the ambiguity they present when assessing the microbial quality of water. FIB can survive and even grow in various environmental reservoirs which means FIB measured in the water column may not have originated directly from a fecal source. Sediment and periphyton, i.e., aquatic biofilms growing on submerged rocks, have been shown to harbor large populations of FIB in the environment. However, little is known about the spatial and temporal dynamics of FIB in periphyton. The objective of this work was to determine levels of the common FIB, Escherichia coli and enterococci, in creek water, sediment, and periphyton during the summer and winter. FIB were measured during two summer and winter sampling dates at five locations along a 2.8-km stretch of creek in Beltsville, Maryland. Significant differences in FIB by location were only observed for E. coli in water at one time point. Levels of FIB significantly declined from summer to winter in all media. FIB concentrations in periphyton ranged from 102 to 104 gdw−1 in the summer and from 100 to 104 CFU gdw−1 in the winter. When compared on a dry weight basis, periphyton contained higher concentrations of FIB than the sediment. Variability of FIB was in the order of water < sediment < periphyton. Levels of E. coli and enterococci measured in the same sample showed significant positive correlation in all media (rs = 0.87, 0.48, 0.70, for water, sediment, and periphyton, respectively). Results from this work show that fecal bacteria can persist in creek periphyton which may act as both a reservoir for fecal pathogens as well as a probable source of fecal bacteria to the water column. [ABSTRACT FROM AUTHOR]