A study protocol for a double-blind randomised placebo-controlled trial evaluating the efficacy of carrageenan nasal and throat spray for COVID-19 prophylaxis-ICE-COVID.

INTRODUCTION: At present, vaccines form the only mode of prophylaxis against COVID-19. The time needed to achieve mass global vaccination and the emergence of new variants warrants continued research into other COVID-19 prevention strategies. The severity of COVID-19 infection is thought to be associated with the initial viral load, and for infection to occur, viruses including SARS-CoV-2 must first penetrate the respiratory mucus and attach to the host cell surface receptors. Carrageenan, a sulphated polysaccharide extracted from red edible seaweed, has shown efficacy against a wide range of viruses in clinical trials through the prevention of viral entry into respiratory host cells. Carrageenan has also demonstrated in vitro activity against SARS-CoV-2. METHODS AND ANALYSIS: A single-centre, randomised, double-blinded, placebo-controlled phase III trial was designed. Participants randomised in a 1:1 allocation to either the treatment arm, verum Coldamaris plus (1.2 mg iota-carrageenan (Carragelose®), 0.4 mg kappa-carrageenan, 0.5% sodium chloride and purified water), or placebo arm, Coldamaris sine (0.5% sodium chloride) spray applied daily to their nose and throat for 8 weeks, while completing a daily symptom tracker questionnaire for a total of 10 weeks. PRIMARY OUTCOME: Acquisition of COVID-19 infection as confirmed by a positive PCR swab taken at symptom onset or seroconversion during the study. Secondary outcomes include symptom type, severity and duration, subsequent familial/household COVID-19 infection and infection with non-COVID-19 upper respiratory tract infections. A within-trial economic evaluation will be undertaken, with effects expressed as quality-adjusted life years. DISCUSSION: This is a single-centre, phase III, double-blind, randomised placebo-controlled clinical trial to assess whether carrageenan nasal and throat spray reduces the risk of development and severity of COVID-19. If proven effective, the self-administered prophylactic spray would have wider utility for key workers and the general population. TRIAL REGISTRATION: NCT04590365; ClinicalTrials.gov NCT04590365. Registered on 19 October 2020.

Species identity dominates over environment in shaping the microbiota of small mammals.

The mammalian gut microbiota is considered pivotal to host fitness, yet the determinants of community composition remain poorly understood. Laboratory studies show that environmental factors, particularly diet, are important, while comparative work emphasises host genetics. Here, we compare the influence of host genetics and the environment on the microbiota of sympatric small mammal species (mice, voles, shrews) across multiple habitats. While sharing a habitat caused some microbiota convergence, the influence of species identity dominated. In all three host genera examined, an individual's microbiota was more similar to conspecifics living elsewhere than to heterospecifics at the same site. Our results suggest this species-specificity arises in part through host-microbe codiversification. Stomach contents analysis suggested that diet also shapes the microbiota, but where diet is itself influenced by species identity. In this way, we can reconcile the importance of both diet and genetics, while showing that species identity is the strongest predictor of microbiota composition.

Rapid through-container detection of fake spirits and methanol quantification with handheld Raman spectroscopy.

The spirits drinks industry is of significant global economic importance and a major employer worldwide, and the ability to ensure product authenticity and maintain consumer confidence in these high-value products is absolutely essential. Spirit drinks counterfeiting is a worldwide problem, with counterfeiting and adulteration of spirit drinks taking many forms, such as substitution, stretching with lower-grade products, or creation of counterfeits with industrial, surrogate, or locally produced alcohols. Methanol for example, which has been used as a substitute alcohol for ethanol, has a high toxicity in humans. The counterfeiting of spirit drinks is consequently one of the few leading reported types of food fraud which can be directly and unequivocally linked to food safety and health concerns. Here, for the first time, we use handheld Raman spectroscopy with excitation in the near IR (1064 nm) for the through-container differentiation of multiple spirit drinks, detection of multiple chemical markers of counterfeit alcohol, and for the quantification of methanol. We established the limits of detection (LOD) of methanol in the analysed samples from four different spirit types (between 0.23-0.39%), which were considerably lower than a quoted maximum tolerable concentration (MTC) of 2% (v/v) methanol for humans in a 40% alcohol by volume (ABV) spirit drink, and even lower than the general EU limit for naturally occurring methanol in fruit spirits of 0.5% v/v (10 g methanol per L ethanol). We believe that Raman spectroscopy has considerable practicable potential for the rapid in situ through-container detection of counterfeit spirits drinks, as well as for the analysis and protection of other beverages and liquid samples.

A simple, quick, validated method of recording the nasal cycle in humans using a subjective scale.

BACKGROUND: Studies on the nasal cycle can be limited by time-consuming rhinomanometric measurements. However, quantifiable subjective assessment of nasal airflow has been limited by poor correlation with rhinomanometric data, even when investigating patients with a deviated nasal septum. METHODS: Thirty healthy participants attended two study days for rhinomanometric and subjective assessment of nasal airflow (using the subjective ordinal scale). A nasal partitioning ratio was calculated for both measures. RESULTS: Objective and subjective nasal partitioning ratios were compared; strong correlations were seen, with a correlation coefficient of 0.64 (p < 0.00001) on day 1 and 0.68 (p < 0.00001) on day 2. CONCLUSION: The use of the subjective ordinal scale and nasal partitioning ratio provides a sensitive tool for assessing relative nasal airflow, with results that correlate strongly with rhinomanometric data. This finding strongly suggests that this combination could be used for future subjective assessment of the nasal cycle.

Is there any relationship between right and left hand dominance and right and left nasal airflow dominance?

BACKGROUND: Left- or right-handedness is a common human trait, and it has been previously reported that human nasal airflow dominance correlates with hand dominance. Any relationship between hand dominance and nasal airflow dominance would be unusual. This study aimed to measure nasal airflow and look for any relationship to handedness. METHODS: The modified Glatzel mirror was used to record the dominant nasal passage at 15-minute intervals over a 6-hour period in 29 healthy participants consisting of 15 left-handers and 14 right-handers. RESULTS: In left-handers, the percentage of time that the left nasal passage was dominant ranged from 0 to 100 per cent. In right-handers, the percentage of time that the right nasal passage was dominant ranged from 4.2 to 95.8 per cent. No correlation between nasal airflow dominance and hand dominance was identified. CONCLUSION: The results do not support the hypothesis that nasal airflow and handedness are related.

Nasal airflow and brain activity: is there a link?

BACKGROUND: Over the past few decades, evidence has emerged suggesting that nasal airflow asymmetry and brain asymmetry are linked. The nose exhibits asymmetrical airflow, with the dominant airflow alternating from one nasal passage to the other over a period of hours. Some authors have suggested a correlation between cerebral hemisphere dominance and nostril dominance. Others have proposed an association between rhythmic fluctuations in nasal airflow and corresponding fluctuations in cerebral hemisphere activity. Based on ancient yoga breathing techniques, newer evidence suggests that altering nasal airflow can influence brain activity, with reports of improved cognitive function caused by unilateral forced nostril breathing. It seems that a nasal airflow stimulus may have an activating effect on the brain, as it has also been shown to trigger seizure activity in epileptic patients. OBJECTIVES: This article explores these theories in detail, reviews the evidence, and presents new models linking nasal airflow and brain activity.

A model for the central control of airflow patterns within the human nasal cycle.

BACKGROUND: The nasal cycle exhibits mainly reciprocal changes in nasal airflow that may be controlled from centres in the hypothalamus and brainstem. This study aims to gather new knowledge about the nasal cycle to help develop a control model. METHOD: Right and left nasal airflow was measured in healthy human subjects by rhinomanometry. This was performed over 7-hour periods on 2 study days separated by approximately 1 week. The correlation coefficient for nasal airflow was calculated for day 1 and day 2. RESULTS: Thirty subjects (mean age, 22.7 years) completed the study. The correlation coefficient for nasal airflow varied between r = 0.97 with in-phase changes in airflow and r = -0.89 with reciprocal changes in airflow. The majority of r values were negative, indicating reciprocal changes in airflow (50 out of 60). There was a tendency for r values to become more negative between day 1 and day 2 (p < 0.001). CONCLUSION: A control model involving a hypothalamic centre and two brainstem half centres is proposed to explain both the in-phase and reciprocal changes in airflow associated with the nasal cycle.

Efficacy and safety of iota-carrageenan nasal spray versus placebo in early treatment of the common cold in adults: the ICICC trial.

UNLABELLED: Iota-carrageenan (I-C) is active against respiratory viruses in vitro and was effective as nasal spray in three previous clinical trials. The current trial served to further investigate I-C in patients with early common cold symptoms. METHODS: This randomized, placebo-controlled, double-blind phase IV trial was conducted in 200 adult patients with self-diagnosed colds of <48 h' duration that were confirmed by baseline cold symptom scores. Patients were to self-administer 0.12 % I-C or placebo spray (NaCl 0.5 %) four times daily for four to ten days and record symptom information for ten days. Common respiratory viruses were quantified by RT-PCR during pretreatment and on Day 3 or 4. The primary endpoint was the mean total symptom score (TSS) of eight cold symptoms on Days 2-4 (TSS2-4). RESULTS: Patients in both treatment groups had similar baseline TSSs (mean TSS: 6.75 for I-C and 6.79 for placebo). Viruses were detected in baseline samples from 53 of 98 I-C patients (54.1 %) and 54 of 97 placebo patients (55.7 %). Mean ± SE for TSS2-4 was 5.78 ± 0.25 for I-C patients and 6.39 ± 0.25 for placebo (p = 0.0895). Exploratory analyses after unblinding (TSS2-4 excluding a patient with aberrantly high symptom scores [TSS2-4, ex 1pt]; mean of TSS over Days 1-4 [TSS1-4]; change in TSS1-4 relative to baseline [TSS1-4, rel]) demonstrated treatment differences in favor of I-C (p = 0.0364, p = 0.0495 and p = 0.0421, respectively). For patients with quantifiable rhinovirus/enterovirus at baseline, there was a trend towards greater reduction of virus load at Day 3 or 4 (p = 0.0958; I-C: 90.2 % reduction in viral load; placebo: 72.0 %). Treatments were well tolerated with no differences in adverse event rates. CONCLUSIONS: The primary endpoint did not demonstrate a statistically significant difference between I-C and placebo but showed a trend towards I-C benefit. Exploratory analyses indicated significant reduction of cold symptoms in the I-C group relative to placebo during the first four days when symptoms were most severe, and also substantiated I-C's activity against rhinovirus/enterovirus. TRIAL REGISTRATION: NCT01944631 (clinicaltrials.gov).

Exposure to cold and acute upper respiratory tract infection.

The incidence of acute upper respiratory tract viral infections (URTI) is directly correlated to air temperature with most URTI occurring seasonally in cold weather. This review looks at four types of cold exposure and examines the evidence and possible mechanisms for any relationship to URTI. The effects of cold are discussed as: 1) Chilling of the nose and upper respiratory tract by breathing cold air, 2) Chilling of the mouth and upper digestive tract by ingestion of cold drinks and food, 3) Acute chilling of the body surface, and, 4) Chilling of the body as a whole with a fall in body temperature, hypothermia. Some studies were found to support a relationship between breathing cold air and chilling the body surface with the development of URTI, although this area is controversial. No evidence was found in the literature to support any relationship between ingestion of cold drinks and food and URTI, and similarly no evidence was found to link hypothermia and URTI.

Assessment of upper airway obstruction by measuring peak oral and nasal inspiratory flow.

OBJECTIVE: We wanted to access upper airway obstruction in patients undergoing tonsillectomy by measuring peak oral and nasal inspiratory airflow. METHODS: We recruited study participants from a cohort of patients on the waiting list for tonsillectomy, with or without adenoidectomy, at University Hospital of Wales, Cardiff, UK. Fifty patients enrolled on phase I of the study and underwent pre-operative measurement of the rate of peak oral and nasal inspiratory flow; 25 of these patients returned after one month for phase II of the study and underwent post-operative measurement of the rate of both peak oral and nasal inspiratory flow. RESULTS: Of the 25 participants who completed phase II of the study, 17 (68 per cent) showed an increase in post-operative peak oral inspiratory flow rate by an average of 45 per cent, while 18 (72 per cent) showed an increase in post-operative peak nasal inspiratory flow rate by an average of 22 per cent. CONCLUSION: Both peak oral and nasal inspiratory flow rate measurements may be useful measures of oral and nasal obstruction. Further larger studies are needed to develop these measurements as screening and efficacy measures for adenotonsillectomy to relieve upper airway obstruction.

Consumer attitudes on cough and cold: US (ACHOO) survey results.

OBJECTIVE: The Attitudes of Consumers Toward Health, Cough, and Cold (ACHOO) survey was developed to better inform health care providers on the natural history and impact of common cold and cough, and related consumer experience and behaviors. RESEARCH DESIGN AND METHODS: Randomly selected US Internet/mobile device users were invited to participate in an online survey (N = 3333) in October 2012. Response quotas modeled upon 2010 US Census data ensured a demographically representative sample. To reduce potential bias from the quota design, 75% of the completed surveys were randomly selected as the primary analysis pool. MAIN OUTCOME MEASURES: Survey questions assessed participant demographics, frequency and duration of cough/cold symptoms, impact of symptoms on daily life, treatment preferences, and knowledge about cough/cold pathophysiology. RESULTS: In the past year, 84.6% of respondents had experienced at least one cold. Colds typically started with sore/scratchy throat (39.2%), nasal congestion (9.8%), and runny nose (9.3%) and lasted 3-7 days. Cough, the most common cold symptom (73.1%), had a delayed onset (typically 1-5 days after cold onset) and a long duration (>6 days in 35.2%). Nasal congestion and cough were the most bothersome symptoms. Many respondents waited until symptoms were 'bad enough' (42.6%) or multiple symptoms were present (20.2%) before using nonprescription medications. Drivers of choice included effectiveness in relieving symptoms, safety, and past experience. Respondents rarely consulted clinicians regarding treatment, and more than three-quarters had never received instructions from a clinician on how to choose a nonprescription cough/cold medication. Misperceptions regarding etiology and treatment of the common cold were prevalent. The main limitation is potential recall bias, since respondents had to recall cough/cold episodes over the prior year. CONCLUSIONS: The ACHOO survey confirms that cold is a common, bothersome experience and that there are gaps in consumers' knowledge of pathophysiology and appropriate management of cough/cold.

Cold pleasure. Why we like ice drinks, ice-lollies and ice cream.

This review discusses how the ingestion of cold foods and drinks may be perceived as pleasant because of the effects of cooling of the mouth. The case is made that man has originated from a tropical environment and that cold stimuli applied to the external skin may initiate thermal discomfort and reflexes such as shivering and vasoconstriction that defend body temperature, whereas cold stimuli applied to the mouth are perceived as pleasant because of pleasure associated with satiation of thirst and a refreshing effect. Cold water is preferred to warm water as a thirst quencher and cold products such as ice cream may also be perceived as pleasant because oral cooling satiates thirst. The case is made that cold stimuli may be perceived differently in the skin and oral mucosa, leading to different effects on temperature regulation, and perception of pleasure or displeasure, depending on the body temperature and the temperature of the external environment.

Is the common cold a clinical entity or a cultural concept?

Common cold is the most common infectious disease of mankind and the term is widely used in the clinical literature as though it were a defined clinical syndrome. Clinical studies on this syndrome often use elaborate symptom scoring systems to diagnose a common cold. The symptom scores are based on a study conducted over 50 years ago to retrospectively diagnose experimental cold and this method cannot be applied to diagnosis of common cold in the community. Diagnosis of the common cold by virology is not feasible because of the number of viruses and the variability in the disease states caused by the viruses. Because of the familiarity of subjects with common cold and the variability in symptomatology it seems a more reasonable approach to use self-diagnosis of common cold for clinical research studies and accept that the common cold is a cultural concept and not a clinical entity.

A review on the mechanism of sore throat in tonsillitis.

BACKGROUND: Sore throat is a common condition associated with acute upper respiratory tract infection, and recurrent episodes of infection may result in chronic tonsillitis. The current UK and USA guidelines for tonsillectomy use the incidence of sore throat episodes as an indication for surgery. However, the mechanism of sore throat is poorly described in the literature. OBJECTIVES: This review will provide basic information for the clinician regarding: the causes, pathophysiology and neurophysiology of sore throat; the mechanism of inflammation; and the role of transient receptor potential ion channels as nociceptors involved in sore throat. The review will present new ideas on the mechanism of ice therapy as an analgesic for post-tonsillectomy pain, and the role of vanilloid and cold receptors.

Safety and Efficacy Profile of Echinacea purpurea to Prevent Common Cold Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial.

Objective. To investigate the safety (risk) and efficacy (benefit) of Echinacea purpurea extract in the prevention of common cold episodes in a large population over a 4-month period. Methods. 755 healthy subjects were allocated to receive either an alcohol extract from freshly harvested E. purpurea (95% herba and 5% root) or placebo. Participants were required to record adverse events and to rate cold-related issues in a diary throughout the investigation period. Nasal secretions were sampled at acute colds and screened for viruses. Results. A total of 293 adverse events occurred with Echinacea and 306 with placebo treatment. Nine and 10% of participants experienced adverse events, which were at least possibly related to the study drug (adverse drug reactions). Thus, the safety of Echinacea was noninferior to placebo. Echinacea reduced the total number of cold episodes, cumulated episode days within the group, and pain-killer medicated episodes. Echinacea inhibited virally confirmed colds and especially prevented enveloped virus infections (P < 0.05). Echinacea showed maximal effects on recurrent infections, and preventive effects increased with therapy compliance and adherence to the protocol. Conclusions. Compliant prophylactic intake of E. purpurea over a 4-month period appeared to provide a positive risk to benefit ratio.

Normal nasal patency: problems in obtaining standard reference values for the surgeon.

This review examines why there is no normal range of nasal patency available to the surgeon when assessing nasal obstruction, and discusses the factors that influence nasal patency. Current normal ranges are examined and criticised because of the variability of normal values and the poor sampling methods used. Instability of physiological nasal patency is related to factors such as the nasal cycle and the nose's direct exposure to the external environment. Decongestion of the nose is proposed as a way of stabilising anatomical nasal patency, and measurements of patency in this state may be more useful to the surgeon. Population studies are needed to establish a normal range, but these studies must control for factors such as age, height, sex, and nasal shape and size related to climatic adaptation. Rather than classify populations according to unscientific categories such as race, anthropometric measures such as the nasal index are proposed.

The relationship between nasal index and nasal airway resistance, and response to a topical decongestant.

The differences in the shape and size of the nose have been proposed to be an adaptation to climate with broad noses (platyrrhine) evolving in a warm humid environment where there was little need for air conditioning and narrow noses (leptorrhine) evolving in colder climates where the air needed more warming. The main aim of this research was to determine if there was any relationship between the shape of the nose as expressed in terms of nasal height and width (nasal index) and total nasal airway resistance (NAR), as one would predict that the narrower leptorrhine noses would have a greater resistance to air flow than the broader platyrrhine noses. It was also proposed that the narrow leptorrhine nose would have better developed vascular tissue than the broad platyrrhine nose in order to condition cold air, and would exhibit a greater response to nasal decongestion. No correlation was found between nasal index and NAR (r = -0.09) and similarly no correlation was found between nasal index and response to a topical nasal decongestant (r = 0.02). The absence of any physiological differences between the different nose types may be due to acclimatisation of participants to the area of recruitment.

Mechanisms of the symptoms of rhinosinusitis.

The review discusses the physiological and pathophysiological mechanisms associated with the symptoms of acute and chronic rhinosinusitis. An understanding of symptom mechanisms is important for the clinical diagnosis of rhinosinusitis and is important in assessing the efficacy of surgical and medical treatments for rhinosinusitis. The review will discuss the four primary symptoms used to diagnose rhinosinusitis: nasal obstruction, nasal discharge, facial pain and loss of sense of smell; and the secondary symptoms, cough, sneezing, sore throat and voice changes, epiphora, fever, and psychological effects and fatigue. The review will highlight that our understanding of a key diagnostic symptoms facial pain is limited, and that the incidence of pain with rhinosinusitis is controversial. Sneezing is a common symptom of acute rhinosinusitis with allergy but is not normally described as symptom in chronic rhinosinusitis and this anomaly is in need of more research. The mechanism of unilateral nasal obstruction with rhinosinusitis is discussed.