A real-world study of quality of life following treatment with xylometazoline hydrochloride in individuals with common cold.

BACKGROUND: The common cold is a frequent, acute, and mild upper respiratory human disease. Nasal congestion has been considered the most bothersome symptom in the common cold, impacting quality of life (QoL). Topical decongestants containing steroids benefit QoL in allergic rhinitis, but no published research has assessed the impact of topical decongestants on QoL in the common cold. OBJECTIVE: To evaluate the effects of xylometazoline hydrochloride 0.1% (Otrivin, GSK Consumer Healthcare SARL, Switzerland) for up to 7 days on QoL in participants with nasal congestion associated with the common cold. DESIGN: This was a decentralized, longitudinal, open-label study. METHODS: The study enrolled 136 participants (⩾18 years) with early symptoms of the common cold, of which 102 were included in the modified intention-to-treat (mITT) population. Within 24 h of study product receipt, participants confirmed a 'plugged nose' and ⩾1 other common cold symptom. Primary endpoints were Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) total score, total and individual symptom scores, and total QoL score. Secondary endpoints were additional QoL scores. Exploratory and post hoc analyses included median days to resolution for each QoL factor and analyses of five QoL categories. RESULTS: Consistent improvements in symptoms and QoL were seen in the mITT population. From day 1, improvements were seen in the 'plugged nose' symptom (p = 0.0023), WURSS-21 total QoL score, and all individual QoL scores (p < 0.0001 for all). After the last dose needed, significant improvements were seen in sleep quality (73%), vitality (76%), physical activity (71%), social activity (80%), and sensation (81%). No serious or unexpected adverse events were reported. CONCLUSION: This study is the first to demonstrate in a real-life setting that treating nasal congestion in adults with xylometazoline hydrochloride 0.1% during the common cold positively impacts QoL factors relevant to daily living [Otrivin: Quality of Life (QoL) Impact in a Real-World Setting; https://clinicaltrials.gov/study/NCT05556148].

Impact of xylometazoline hydrochloride 0.1% on quality of life in people with blocked nose associated with the common coldThe common cold is a widespread, mild respiratory illness for which a hallmark symptom is a blocked or stuffy nose, which makes breathing and sleeping difficult. This study focused on how a nasal spray called Otrivin (containing xylometazoline hydrochloride 0.1%) impacts the quality of life (QoL) of people suffering from nasal congestion due to the common cold.Participants answered a questionnaire called the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21), which helped understand how people experience respiratory symptoms and how different aspects of QoL were impacted. Participants also responded to eight additional QoL questions not covered in the WURSS-21.The results showed that from the first day of using the nasal spray, participants experienced significant relief from the blocked nose symptom and reported an overall improvement in their QoL and well-being, such as in sleep quality, energy levels, senses, and physical and social activities.In conclusion, this real-world study demonstrated that using xylometazoline hydrochloride 0.1% nasal spray during the common cold can significantly improve nasal congestion and various aspects of a person's daily life. These findings provide valuable evidence for using this nasal spray to relieve symptoms and enhance the overall well-being of individuals with the common cold.

Safety and Performance of Narhinel 0.9% Sodium Chloride Monodose and Otrisal 0.74% Sodium Chloride Monodose Nasal Saline Solutions and Nasal Aspirators in Real-World Settings: Postmarket Clinical Follow-up Study Results.

Background: Blocked or stuffy nose is a common and bothersome symptom of colds, particularly for young children who are unable to clear their noses on their own. Nasal saline solutions and nasal aspirators are designed to gently cleanse and remove blocking nasal secretions. Objective: To assess the safety and performance of 2 monodose isotonic saline solutions (Narhinel 0.9% and Otrisal 0.74% sodium chloride; GSK Consumer Healthcare SARL, a Haleon company, Nyon, Switzerland) and 2 nasal aspirators with disposable hard- and soft-nozzle refills used as a standalone or combination treatment. Methods: We conducted 2 observational, online questionnaire-based, postmarket clinical follow-up studies in Europeans who had used any of the devices ≥1 time in the past 6 months. Coprimary objectives were to confirm the safety and performance of the saline solutions (Narhinel and Otrisal, Study 1) and nasal aspirators (with hard- and soft-nozzle refills, Study 2). Safety was assessed via the proportion of patients reporting adverse events and/or device malfunctions while using the devices within the previous 6 months, and performance was assessed by satisfaction rated on a 5-point scale, with "satisfied" and "very satisfied" being the highest performance ratings. Results: A total of 1136 (Study 1) and 1237 (Study 2) questionnaires were initiated by volunteer participants. Less than 2% of participants reported adverse events for any evaluated product in the previous 6 months. Most participants were "satisfied" or "very satisfied" with the devices for their intended use, with 78% to 91% of participants in the Narhinel arm, 73%-94% in the Otrisal arm, 71% to 95% in the soft-nozzle arm, and 71% to 80% in the hard-nozzle arm giving these ratings. Conclusions: These data support the safety and performance of 2 monodose saline solutions (Narhinel and Otrisal) for nasal cleansing, nasal moisturization, and/or loosening nasal secretions, and of nasal aspirators (with hard- and soft-nozzle refills) for clearing a blocked nose and removing nasal secretions.

Perirhinal cortex lesions in rats: Novelty detection and sensitivity to interference.

Rats with perirhinal cortex lesions received multiple object recognition trials within a continuous session to examine whether they show false memories. Experiment 1 focused on exploration patterns during the first object recognition test postsurgery, in which each trial contained 1 novel and 1 familiar object. The perirhinal cortex lesions reduced time spent exploring novel objects, but did not affect overall time spent exploring the test objects (novel plus familiar). Replications with subsequent cohorts of rats (Experiments 2, 3, 4.1) repeated this pattern of results. When all recognition memory data were combined (Experiments 1-4), giving totals of 44 perirhinal lesion rats and 40 surgical sham controls, the perirhinal cortex lesions caused a marginal reduction in total exploration time. That decrease in time with novel objects was often compensated by increased exploration of familiar objects. Experiment 4 also assessed the impact of proactive interference on recognition memory. Evidence emerged that prior object experience could additionally impair recognition performance in rats with perirhinal cortex lesions. Experiment 5 examined exploration levels when rats were just given pairs of novel objects to explore. Despite their perirhinal cortex lesions, exploration levels were comparable with those of control rats. While the results of Experiment 4 support the notion that perirhinal lesions can increase sensitivity to proactive interference, the overall findings question whether rats lacking a perirhinal cortex typically behave as if novel objects are familiar, that is, show false recognition. Rather, the rats retain a signal of novelty but struggle to discriminate the identity of that signal.

Advances in the behavioural testing and network imaging of rodent recognition memory.

Research into object recognition memory has been galvanised by the introduction of spontaneous preference tests for rodents. The standard task, however, contains a number of inherent shortcomings that reduce its power. Particular issues include the problem that individual trials are time consuming, so limiting the total number of trials in any condition. In addition, the spontaneous nature of the behaviour and the variability between test objects add unwanted noise. To combat these issues, the 'bow-tie maze' was introduced. Although still based on the spontaneous preference of novel over familiar stimuli, the ability to give multiple trials within a session without handling the rodents, as well as using the same objects as both novel and familiar samples on different trials, overcomes key limitations in the standard task. Giving multiple trials within a single session also creates new opportunities for functional imaging of object recognition memory. A series of studies are described that examine the expression of the immediate-early gene, c-fos. Object recognition memory is associated with increases in perirhinal cortex and area Te2 c-fos activity. When rats explore novel objects the pathway from the perirhinal cortex to lateral entorhinal cortex, and then to the dentate gyrus and CA3, is engaged. In contrast, when familiar objects are explored the pathway from the perirhinal cortex to lateral entorhinal cortex, and then to CA1, takes precedence. The switch to the perforant pathway (novel stimuli) from the temporoammonic pathway (familiar stimuli) may assist the enhanced associative learning promoted by novel stimuli.

Association rules for rat spatial learning: the importance of the hippocampus for binding item identity with item location.

Three cohorts of rats with extensive hippocampal lesions received multiple tests to examine the relationships between particular forms of associative learning and an influential account of hippocampal function (the cognitive map hypothesis). Hippocampal lesions spared both the ability to discriminate two different digging media and to discriminate two different room locations in a go/no-go task when each location was approached from a single direction. Hippocampal lesions had, however, differential effects on a more complex task (biconditional discrimination) where the correct response was signaled by the presence or absence of specific cues. For all biconditional tasks, digging in one medium (A) was rewarded in the presence of cue C, while digging in medium B was rewarded in the presences of cue D. Such biconditional tasks are "configural" as no individual cue or element predicts the solution (AC+, AD-, BD+, and BC-). When proximal context cues signaled the correct digging choice, biconditional learning was seemingly unaffected by hippocampal lesions. Severe deficits occurred, however, when the correct digging choice was signaled by distal room cues. Also, impaired was the ability to discriminate two locations when each location was approached from two directions. A task demand that predicted those tasks impaired by hippocampal damage was the need to combine specific cues with their relative spatial positions ("structural learning"). This ability makes it possible to distinguish the same cues set in different spatial arrays. Thus, the hippocampus appears necessary for configural discriminations involving structure, discriminations that potentially underlie the creation of cognitive maps.

The neural basis of nonvisual object recognition memory in the rat.

Research into the neural basis of recognition memory has traditionally focused on the remembrance of visual stimuli. The present study examined the neural basis of object recognition memory in the dark, with a view to determining the extent to which it shares common pathways with visual-based object recognition. Experiment 1 assessed the expression of the immediate-early gene c-fos in rats that discriminated novel from familiar objects in the dark (Group Novel). Comparisons made with a control group that explored only familiar objects (Group Familiar) showed that Group Novel had higher c-fos activity in the rostral perirhinal cortex and the lateral entorhinal cortex. Outside the temporal region, Group Novel showed relatively increased c-fos activity in the anterior medial thalamic nucleus and the anterior cingulate cortex. Both the hippocampal CA fields and the granular retrosplenial cortex showed borderline increases in c-fos activity with object novelty. The hippocampal findings prompted Experiment 2. Here, rats with hippocampal lesions were tested in the dark for object recognition memory at different retention delays. Across two replications, no evidence was found that hippocampal lesions impair nonvisual object recognition. The results indicate that in the dark, as in the light, interrelated parahippocampal sites are activated when rats explore novel stimuli. These findings reveal a network of linked c-fos activations that share superficial features with those associated with visual recognition but differ in the fine details; for example, in the locus of the perirhinal cortex activation. While there may also be a relative increase in c-fos activation in the extended-hippocampal system to object recognition in the dark, there was no evidence that this recognition memory problem required an intact hippocampus.

Evidence that the rat hippocampus has contrasting roles in object recognition memory and object recency memory.

Adult rats with extensive, bilateral neurotoxic lesions of the hippocampus showed normal forgetting curves for object recognition memory, yet were impaired on closely related tests of object recency memory. The present findings point to specific mechanisms for temporal order information (recency) that are dependent on the hippocampus and do not involve object recognition memory. The object recognition tests measured rats exploring simultaneously presented objects, one novel and the other familiar. Task difficulty was varied by altering the retention delays after presentation of the familiar object, so creating a forgetting curve. Hippocampal lesions had no apparent effect, despite using an apparatus (bow-tie maze) where it was possible to give lists of objects that might be expected to increase stimulus interference. In contrast, the same hippocampal lesions impaired the normal preference for an older (less recent) familiar object over a more recent, familiar object. A correlation was found between the loss of septal hippocampal tissue and this impairment in recency memory. The dissociation in the present study between recognition memory (spared) and recency memory (impaired) was unusually compelling, because it was possible to test the same objects for both forms of memory within the same session and within the same apparatus. The object recency deficit is of additional interest as it provides an example of a nonspatial memory deficit following hippocampal damage.

Contrasting brain activity patterns for item recognition memory and associative recognition memory: insights from immediate-early gene functional imaging.

Recognition memory, the discrimination of a novel from a familiar event, can be classified into item recognition and associative recognition. Item recognition concerns the identification of novel individual stimuli, while associative recognition concerns the detection of novelty that arises when familiar items are reconfigured in a novel manner. Experiments in rodents that have mapped the expression of immediate-early genes, e.g., c-fos, highlight key differences between these two forms of recognition memory. Visual item novelty is consistently linked to increased c-fos activity in just two brain sites, the perirhinal cortex and the adjacent visual association area Te2. Typically there are no hippocampal c-fos changes. In contrast, visual associative recognition is consistently linked to c-fos activity changes in the hippocampus, but not the perirhinal cortex. The lack of a c-fos perirhinal change with associative recognition presumably reflects the fact that the individual items in an array remain familiar, even though their combinations are unique. Those exceptions, when item recognition is associated with hippocampal c-fos changes, occur when rats actively explore novel objects. The increased engagement with objects will involve multisensory stimulus processing and potentially create conditions in which rats can readily learn stimulus attributes such as object location or object order, i.e., attributes involved in associative recognition. Correlations based on levels of immediate-early gene expression in the temporal lobe indicate that actively exploring novel stimuli switches patterns of entorhinal-hippocampal functional connectivity to emphasise direct entorhinal-dentate gyrus processing. These gene activity findings help to distinguish models of medial temporal lobe function.

Separate but interacting recognition memory systems for different senses: the role of the rat perirhinal cortex.

Two different models (convergent and parallel) potentially describe how recognition memory, the ability to detect the re-occurrence of a stimulus, is organized across different senses. To contrast these two models, rats with or without perirhinal cortex lesions were compared across various conditions that controlled available information from specific sensory modalities. Intact rats not only showed visual, tactile, and olfactory recognition, but also overcame changes in the types of sensory information available between object sampling and subsequent object recognition, e.g., between sampling in the light and recognition in the dark, or vice versa. Perirhinal lesions severely impaired object recognition whenever visual cues were available, but spared olfactory recognition and tactile-based object recognition when tested in the dark. The perirhinal lesions also blocked the ability to recognize an object sampled in the light and then tested for recognition in the dark, or vice versa. The findings reveal parallel recognition systems for different senses reliant on distinct brain areas, e.g., perirhinal cortex for vision, but also show that: (1) recognition memory for multisensory stimuli involves competition between sensory systems and (2) perirhinal cortex lesions produce a bias to rely on vision, despite the presence of intact recognition memory systems serving other senses.

Perirhinal cortex lesions uncover subsidiary systems in the rat for the detection of novel and familiar objects.

The present study compared the impact of perirhinal cortex lesions on tests of object recognition. Object recognition was tested directly by looking at the preferential exploration of novel objects over simultaneously presented familiar objects. Object recognition was also tested indirectly by presenting just novel objects or just familiar objects, and recording exploration levels. Rats with perirhinal cortex lesions were severely impaired at discriminating a novel object from a simultaneously presented familiar object (direct test), yet displayed normal levels of exploration to novel objects presented on their own and showed normal declines in exploration times for familiar objects that were repeatedly presented (indirect tests). This effective reduction in the exploration of familiar objects after perirhinal cortex lesions points to the sparing of some recognition mechanisms. This possibility led us to determine whether rats with perirhinal cortex lesions can overcome their preferential exploration deficits when given multiple object familiarisation trials prior to that same (familiar) object being paired with a novel object. It was found that after multiple familiarisation trials, objects could now successfully be recognised as familiar by rats with perirhinal cortex lesions, both following a 90-min delay (the longest delay tested) and when object recognition was tested in the dark after familiarisation trials in the light. These latter findings reveal: (i) the presumed recruitment of other regions to solve recognition memory problems in the absence of perirhinal cortex tissue; and (ii) that these additional recognition mechanisms require more familiarisation trials than perirhinal-based recognition mechanisms.

Hippocampus and neocortex: recognition and spatial memory.

Recognition and spatial memory are typically associated with the perirhinal cortex and hippocampal formation, respectively. Solely focusing on these structures for these specific mnemonic functions may, however, be limiting progress in the field. The distinction between these subdivisions of memory is becoming less defined as, for example, hippocampal cells traditionally considered to encode locations also encode place-object associations. There is increasing evidence for the involvement of overlapping networks of brain structures for aspects of both spatial and recognition memory. Future models of spatial and recognition memory will have to extend beyond the hippocampus and perirhinal cortex to incorporate a wider network of cortical and subcortical structures.

New behavioral protocols to extend our knowledge of rodent object recognition memory.

Animals often show an innate preference for novelty. This preference facilitates spontaneous exploration tasks of novelty discrimination (recognition memory). In response to limitations with standard spontaneous object recognition procedures for rodents, a new task ("bow-tie maze") was devised. This task combines features of delayed nonmatching-to-sample with spontaneous exploration. The present study explored aspects of object recognition in the bow-tie maze not amenable to standard procedures. Two rat strains (Lister Hooded, Dark Agouti) displayed very reliable object recognition in both the light and dark, with the Lister Hooded strain showing superior performance (Experiment 1). These findings reveal the potential contribution of tactile and odor cues in object recognition. As the bow-tie maze task permits multiple trials within a session, it was possible to derive forgetting curves both within-session and between-sessions (Experiment 1). In Experiment 2, rats with hippocampal or fornix lesions performed at normal levels on the basic version of the recognition task, contrasting with the marked deficits previously seen after perirhinal cortex lesions. Next, the training protocol was adapted (Experiment 3), and this modified version was used successfully with mice (Experiment 4). The overall findings demonstrate the efficacy of this new behavioral task and advance our understanding of object recognition.

Lesions of the perirhinal cortex do not impair integration of visual and geometric information in rats.

Rats with lesions of the perirhinal cortex and a control group were required to find a platform in 1 corner of a white rectangle and in the reflection of this corner in a black rectangle. Test trials revealed that these groups were able to integrate information regarding the shape of the pool and the color of its walls (black or white) to identify the correct location of the platform. A clear effect of the perirhinal cortex lesions was, however, revealed using an object recognition task that involved the spontaneous exploration of novel objects. The results challenge the view that the perirhinal cortex enables rats to solve discriminations involving feature ambiguity.

Lesions of the rat perirhinal cortex spare the acquisition of a complex configural visual discrimination yet impair object recognition.

Rats with perirhinal cortex lesions were sequentially trained in a rectangular water tank on a series of 3 visual discriminations, each between mirror-imaged stimuli. When these same discriminations were tested concurrently, the rats were forced to use a configural strategy to solve the problems effectively. There was no evidence that lesions of the perirhinal cortex disrupted the ability to learn the concurrent configural discrimination task, which required the rats to learn the precise combination of stimulus identity with stimulus placement ("structural" learning). The same rats with perirhinal cortex lesions were also unimpaired on a test of spatial working memory (reinforced T maze alternation), although they were markedly impaired on a new test of spontaneous object recognition. For the recognition test, rats received multiple trials within a single session in which on every trial, they were allowed to explore 2 objects, 1 familiar, the other novel. On the basis of their differential exploration times, rats with perirhinal cortex lesions showed very poor discrimination of the novel objects, thereby confirming the effectiveness of the surgery. The discovery that bilateral lesions of the perirhinal cortex can leave configural (structural) learning seemingly unaffected points to a need to refine those models of perirhinal cortex function that emphasize its role in representing conjunctions of stimulus features.

Qualitatively different modes of perirhinal-hippocampal engagement when rats explore novel vs. familiar objects as revealed by c-Fos imaging.

Expression of the immediate-early gene c-fos was used to test for different patterns of temporal lobe interactions when rats explore either novel or familiar objects. A new behavioural test of recognition memory was first devised to generate robust levels of novelty discrimination and to provide a matched control condition using familiar objects. Increased c-Fos activity was found in caudal but not rostral portions of the perirhinal cortex (areas 35/36) and in area Te2 in rats showing object recognition, i.e. preferential exploration of novel vs. familiar objects. The findings are presented at a higher anatomical resolution than previous studies of immediate-early gene expression and object novelty and, crucially, provide the first analyses when animals are actively discriminating the novel objects. Novel vs. familiar object comparisons also revealed altered c-Fos patterns in hippocampal subfields, with relative increases in CA3 and CA1 and decreases in the dentate gyrus. These hippocampal changes match those previously reported for the automatic coding of object-spatial associations. Additional analyses of the c-Fos data using structural equation modelling indicated the presence of pathways starting in the caudal perirhinal cortex that display a direction of effects from the entorhinal cortex to the CA1 field (temporo-ammonic) when presented with familiar objects, but switch to the engagement of the direct entorhinal cortex pathway to the dentate gyrus (perforant) with novel object discrimination. This entorhinal switch provides a potential route by which the rhinal cortex can moderate hippocampal processing, with a dynamic change from temporo-ammonic (familiar stimuli) to perforant pathway (novel stimuli) influences.

Granular and dysgranular retrosplenial cortices provide qualitatively different contributions to spatial working memory: evidence from immediate-early gene imaging in rats.

The present study revealed striking task-dependent differences in immediate-early gene activity in the two main subregions (granular and dysgranular) of the retrosplenial cortex. In addition, there were activity differences along the rostro-caudal axis of both subregions. Two groups of rats were trained on a working memory task in a radial-arm maze, one group in the light, the other in the dark. Each working memory group had two sets of yoked controls. Working memory consistently increased retrosplenial immediate-early gene activity (c-fos and zif268 ), although systematic differences occurred in the granular and dysgranular subregions. Both c-fos and zif268 expression increased in granular cortex irrespective of whether the spatial memory task was in the light or dark. In contrast, only in the light did spatial memory increase dysgranular cortex activation. Correlations based on the counts of Fos-positive cells helped to reinforce the particular association between the dysgranular retrosplenial cortex and radial-arm maze performance in the light. These results provide clear evidence for proposed functional differences between the major retrosplenial subregions: the granular cortex contributes to spatial learning and navigation based on both internal and external cues (light and dark), while dysgranular cortex is more selectively involved when distal visual cues control performance (light only).

Hippocampal, retrosplenial, and prefrontal hypoactivity in a model of diencephalic amnesia: Evidence towards an interdependent subcortical-cortical memory network.

The medial diencephalon is vital for memory, but it is not known why. The present study tested between the predictions of current hypotheses as to why this region is critical for memory. Lesions were made in the rat mammillothalamic tract, the only diencephalic structure consistently associated with amnesia in humans after ischemia. Decreased activity, as measured by immediate-early gene expression (c-fos), was found in three key sites associated with memory function: the hippocampus, the prefrontal cortex, and the retrosplenial cortex. The specificity of these changes was confirmed by the qualitatively different patterns of immediately-early gene changes seen after amygdala lesions, e.g., hypoactivity in the hippocampus and retrosplenial cortex following mammillothalamic tract lesions but not following amygdala lesions. The mammillothalamic lesion results unify substrates linked to diencephalic and temporal lobe amnesia, and thereby support a new account of diencephalic amnesia that emphasizes multiple dysfunctions across hippocampal, retrosplenial, and prefrontal areas. This account suggests a role for the mammillary bodies that is independent of their hippocampal inputs.

Hippocampal lesions halve immediate-early gene protein counts in retrosplenial cortex: distal dysfunctions in a spatial memory system.

The present study examined whether hippocampal lesions disrupt retrosplenial cortex function. The immediate-early genesc-fos and zif268 provided markers of cellular activity, and their levels were compared in different cytoarchitectonic subregions (dysgranular, granular a and granular b) and different layers (superficial or deep) within retrosplenial cortex. Experiments 1-3 examined the impact of hippocampal lesions on retrosplenial cortex function, with the variations in protocol (e.g. lesion method, rat strain, behaviour prior to gene activity measurement) testing the generality of the findings. Experiment 1 showed that radio-frequency hippocampus lesions result in very striking losses of Fos and Zif268 activity in both superficial and deep laminae of all retrosplenial subregions. This pattern of results was repeated for Fos in experiments 2 and 3. Despite the loss of Fos and Zif268, there was no evidence of retrosplenial cortex atrophy as measured by Nissl counts (experiments 1-3) or NeuN-positive cell counts (experiment 3). Likewise, there was little evidence of any overt changes in cellular size, shape or appearance. The specificity of these hippocampal lesion effects was confirmed in experiment 4 as entorhinal cortex lesions did not change retrosplenial Fos levels. These results provide strong support for the notion that the retrosplenial cortex is unusually sensitive to deafferentation from some of its inputs, so that hippocampal damage might produce permanent 'covert pathology' in the retrosplenial cortex. Such dysfunctions could contribute to the pattern of cognitive changes associated with hippocampal lesions and also help to explain the functional interdependency of these two structures.