The feasibility of home monitoring of young people with cystic fibrosis: Results from CLIMB-CF.

BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.

NICO Phase II clinical trial - focus on an emerging immunotherapy strategy for the adjuvant treatment of locally-advanced oral cancers.

Outcomes remain poor for patients presenting with locally-advanced oral cancers and it remains imperative to re-evaluate adjuvant therapies to provide improved outcomes, ideally without compromising on long-term quality of life. We present current available evidence that supports the use of immune checkpoint inhibitors (ICI) in squamous cell carcinoma (SCC) of the head and neck and discuss trials examining the integration of ICI into the locoregional management of such lesions that are resectable. We focus particularly on the Neoadjuvant and adjuvant nivolumab as Immune Checkpoint inhibition in Oral cavity cancer (NICO) trial which is investigating the integration of neoadjuvant and adjuvant ICI into the treatment of resectable locally-advanced oral cavity cancers.

Adjuvant management of locally advanced oral squamous cell carcinoma - real-world challenges and opportunities.

Patients with locally advanced oral squamous cell cancer (LAOSCC) are treated with adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) following surgical ablation. This depends on the pathological risk factors and aims to reduce the risk of local recurrence and improve survival. Delivery of these aggressive treatments is, however, challenging particularly following major surgery. To inform the adaptations necessary to deliver gold-standard therapy, we aimed to describe real-world delivery of multimodality treatment in LAOSCC, in a UK population with high levels of disease incidence and low socioeconomic status. Patients with LAOSCC (T1-4 N1-3/T3-4 N0) who were treated between October 2014 and October 2016 and had a minimum follow up of 24 months were included. They were identified using the Somerset Cancer Register and data were collected through retrospective case note review. Approval was obtained from the audit departments at the relevant NHS institutions, and data were analysed using IBM SPSS Statistics for Windows version 24 (IBM Corp). The analysis included 129 patients with 82% having an initial performance status (PS) of 0-1. The most frequent change in PS was a one point drop (46%). Twenty of the 93 eligible patients (22%) underwent adjuvant CRT. A total of 37 (40%) began adjuvant CRT/RT within 42 days, and 79 (85%) within 56 days. A delay in initiating adjuvant therapy was associated with higher rates of complications and a longer postoperative hospital stay. Concordance between imaging and pathological nodal staging was poor (cK 0.223). PS frequently declines after complex surgical procedures and long postoperative recovery periods, leading to difficulties providing adjuvant treatments within the national guidance of 42 days. Frequent deviation from planned adjuvant therapies highlights the need for improved treatment strategies.

Early inherited risk for anxiety moderates the association between fathers' child-centered parenting and early social inhibition.

Studies of the role of the early environment in shaping children's risk for anxiety problems have produced mixed results. It is possible that inconsistencies in previous findings result from a lack of consideration of a putative role for inherited influences moderators on the impact of early experiences. Early inherited influences not only contribute to vulnerabilities for anxiety problems throughout the lifespan, but can also modulate the ways that the early environment impacts child outcomes. In the current study, we tested the effects of child-centered parenting behaviors on putative anxiety risk in young children who differed in levels of inherited vulnerability. We tested this using a parent-offspring adoption design and a sample in which risk for anxiety problems and parenting behaviors were assessed in both mothers and fathers. Inherited influences on anxiety problems were assessed as anxiety symptoms in biological parents. Child-centered parenting was observed in adoptive mothers and fathers when children were 9 months old. Social inhibition, an early temperament marker of anxiety risk, was observed at child ages 9 and 18 months. Inherited influences on anxiety problems moderated the link between paternal child-centered parenting during infancy and social inhibition in toddlerhood. For children whose birth parents reported high levels of anxiety symptoms, greater child-centered parenting in adoptive fathers was related to greater social inhibition 9 months later. For children whose birth parents reported low levels of anxiety symptoms, greater child-centered parenting in adoptive fathers was related to less social inhibition across the same period.

First description of the neuro-anatomy of a larval coral reef fish Amphiprion ocellaris.

The present study described the neuro-anatomy of a larval coral reef fish Amphiprion ocellaris and hypothesized that morphological changes during the transition from the oceanic environment to a reef environment (i.e. recruitment) have the potential to be driven by changes to environmental conditions and associated changes to cognitive requirements. Quantitative comparisons were made of the relative development of three specific brain areas (telencephalon, mesencephalon and cerebellum) between 6 days post-hatch (dph) larvae (oceanic phase) and 11 dph (at reef recruitment). The results showed that 6 dph larvae had at least two larger structures (telencephalon and mesencephalon) than 11 dph larvae, while the size of cerebellum remained identical. These results suggest that the structure and organization of the brain may reflect the cognitive demands at every stage of development. This study initiates analysis of the relationship between behavioural ecology and neuroscience in coral reef fishes.

Alpine cushion plants inhibit the loss of phylogenetic diversity in severe environments.

Biotic interactions can shape phylogenetic community structure (PCS). However, we do not know how the asymmetric effects of foundation species on communities extend to effects on PCS. We assessed PCS of alpine plant communities around the world, both within cushion plant foundation species and adjacent open ground, and compared the effects of foundation species and climate on alpha (within-microsite), beta (between open and cushion) and gamma (open and cushion combined) PCS. In the open, alpha PCS shifted from highly related to distantly related with increasing potential productivity. However, we found no relationship between gamma PCS and climate, due to divergence in phylogenetic composition between cushion and open sub-communities in severe environments, as demonstrated by increasing phylo-beta diversity. Thus, foundation species functioned as micro-refugia by facilitating less stress-tolerant lineages in severe environments, erasing a global productivity - phylogenetic diversity relationship that would go undetected without accounting for this important biotic interaction.

Diets of coral-dwelling fishes of the genus Gobiodon with evidence of corallivory.

Evidence of facultative corallivory is documented in three species of obligate coral-dwelling gobies (genus Gobiodon) based on the presence of spirocysts in gut contents. Coral-dwelling gobies also consumed a broad range of other items with gut contents dominated by algae, invertebrates and amorphous material. Dietary similarities between species suggest corallivory may be widespread in this genus.

Catheter related bloodstream infection following PICC removal in preterm infants.

OBJECTIVE: Describe the incidence of catheter-related blood stream infection (CRBSI), following removal of peripherally inserted central venous catheters (PICC) in preterm infants. STUDY DESIGN: A retrospective cohort study of infants <29 weeks gestational age with a PICC revealed 101 PICCs placed (2159 PICC days). Patients were hospitalized in a level III Neonatal Intensive Care Unit (NICU) between January 2002 and December 2003. Chi(2) analysis was performed. RESULTS: One infection was detected after the removal of a PICC (1 per 202 days). Ten infants had a CRBSI attributed to a PICC (1 per 216 PICC days). CRBSI during indwelling PICC was associated with increased risk for sepsis evaluation after PICC removal (P<0.05). CONCLUSIONS: The incidence of CRBSI in the 48 h following PICC removal was not different than the incidence of CRBSI while a PICC was in-dwelling. There was no evidence from this study to support antibacterial prophylaxis before PICC removal.

Unsuspected transection of lung by pigtail catheter in a premature infant.

Thoracostomy tubes are commonly required to treat pnuemothoraces in premature infants. Evidence of impalement of the lungs by tube thoracostomy has been seen in autopsy studies. In neonates, there has been described a surprisingly high incidence of lung perforation. The premature lung is thought to be at greater risk for this complication owing to the pliant, thin chest wall, the proximity of vital tissues and the fragility of the lung tissue itself. The modified Fuhrman catheter, or polyurethane pigtail catheter, has been developed for the drainage of pneumothorax in premature infants. In a study of complications of the placement of pigtail catheters, no instance of penetration of the lungs was reported. We report the case of a premature infant with pigtail catheter placement that, at autopsy, was found to have impaled the lung and discuss the incidence of lung injury associated with invasive management of pnuemothoraces.

Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and secondary hyperalgesia.

OBJECTIVE: In the present study, we sought to develop/characterize the pain profile of a rat model of surgically induced osteoarthritis (OA). METHODS: OA was surgically induced in male Lewis rats (200-225 g) by transection of the medial collateral ligament and medial meniscus of the femoro-tibial joint. In order to characterize the pain profile, animals were assessed for a change in hind paw weight distribution (HPWD), development of mechanical allodynia, and the presence of thermal and mechanical hyperalgesia. Rofecoxib and gabapentin were examined for their ability to decrease change in weight distribution and tactile allodynia. RESULTS: Transection of the medial collateral ligament and medial meniscus of male Lewis rats resulted in rapid (<3 days) changes in hind paw weight bearing and the development of tactile allodynia (secondary hyperalgesia). There was, however, no appreciable effect on thermal hyperalgesia or mechanical hyperalgesia. Treatment with a single dose of rofecoxib (10 mg/kg, PO, day 21 post surgery) or gabapentin (100mg/kg, PO, day 21 post surgery) significantly attenuated the change in HPWD, however, only gabapentin significantly decreased tactile allodynia. CONCLUSION: The rat medial meniscal tear (MMT) model mimics both nociceptive and neuropathic OA pain and is responsive to both a selective cylooxygenase-2 (COX-2) inhibitor commonly utilized for OA pain (rofecoxib) and a widely prescribed drug for neuropathic pain (gabapentin). The rat MMT model may therefore represent a predictive tool for the development of pharmacologic interventions for the treatment of the symptoms associated with OA.

The distribution of positive and negative species interactions across environmental gradients on a dual-lattice model.

There has been considerable recent interest in understanding the role of positive inter-specific interactions within ecology, and significant progress has been made both empirically and theoretically. Similarly, considerable progress has been made in improving our understanding of the mechanisms that limit species' ranges. In this contribution, we seek to understand the setting of species' borders when some species within the assemblage exhibit positive inter-specific interactions. We use a spatially explicit dual-lattice simulation model to explore the distribution of different interactions across environmental gradients. We first simulate community dynamics when there is either a gradient in reproductive rate or in mortality. We then consider what happens when gradients in reproduction and mortality run in parallel or perpendicular to one another. If the stress gradient impacts on reproductive potential, positive interactions are found where there is high abiotic stress. In this instance, the mutualists are able to tolerate an environment that the cheaters cannot. However, when the stress gradient influences mortality, we find that the mutualists occur as a stripe surrounded by cheaters both towards the better and the harsher ends of the gradient. Previous theory and most empirical evidence tend to indicate that net positive interactions are likely to occur in environments characterized by high abiotic stress. However, evidence from some stress gradients suggests that the distribution of positive and negative interactions can be more complex, with the most stressful environments being occupied by individuals engaging in negative rather than positive interactions. Our results provide a potential theoretical explanation for these recent field observation, and highlight the need for further theoretical and empirical work to better our understanding of how positive and negative interactions act to determine the limits to species' ranges.

The interplay of positive and negative species interactions across an environmental gradient: insights from an individual-based simulation model.

Positive interspecific interactions are commonplace, and in recent years ecologists have begun to realize how important they can be in determining community and ecosystem dynamics. It has been predicted that net positive interactions are likely to occur in environments characterized by high abiotic stress. Although empirical field studies have started to support these predictions, little theoretical work has been carried out on the dynamic nature of these effects and their consequences for community structure. We use a simple patch-occupancy model to simulate the dynamics of a pair of species living on an environmental gradient. Each of the species can exist as either a mutualist or a cheater. The results confirm the prediction: a band of mutualists tends to occur in environmental conditions beyond the limits of the cheaters. The region between mutualists and cheaters is interesting: population density here is low. Mutualists periodically occupy this area, but are displaced by cheaters, who themselves go extinct in the absence of the mutualists. Furthermore, the existence of mutualists extends the area occupied by the cheaters, essentially increasing their realized niche. Our approach has considerable potential for improving our understanding of the balance between positive and negative interspecific interactions and for predicting the probable impacts of habitat loss and climate change on communities dominated by positive interspecific interactions.

Environmental changes in the North Atlantic Region: SCANNET as a collaborative approach for documenting, understanding and predicting changes.

The lands surrounding the North Atlantic Region (the SCANNET Region) cover a wide range of climate regimes, physical environments and availability of natural resources. Except in the extreme North, they have supported human populations and various cultures since at least the end of the last ice age. However, the region is also important at a wider geographical scale in that it influences the global climate and supports animals that migrate between the Arctic and all the other continents of the world. Climate, environment and land use in the region are changing rapidly and projections suggest that global warming will be amplified there while increasing land use might dramatically reduce the remaining wilderness areas. Because much of the region is sparsely populated--if populated at all--observational records of past environmental changes and their impacts are both few and of short duration. However, it is becoming very important to record the changes that are now in progress, to understand the drivers of these changes, and to predict future consequences of the changes. To facilitate research into understanding impacts of global change on the lands of the North Atlantic Regions, and also to monitor changes in real time, an EU-funded network of research sites and infrastructures was formed in 2000: this was called SCANNET--SCANdinavian/North European NETwork of Terrestrial Field Bases. SCANNET currently consists of 9 core sites and 5 sites within local networks that together cover the broad range of current climate and predicted change in the region. Climate observations are well replicated across the network, whereas each site has tended to select particular environmental and ecological subjects for intensive observation. This provides diversity of both subject coverage and expertise. In this paper, we summarize the findings of SCANNET to-date and outline its information bases in order to increase awareness of data on environmental change in the North Atlantic Region. We also identify important gaps in our understanding and identify where the roles of existing infrastructures and activities represented by SCANNET can facilitate future research, monitoring and ground-truthing activities.

Control of H+/lactose coupling by ionic interactions in the lactose permease of Escherichia coli.

A combinatorial approach was used to study putative interactions among six ionizable residues (Asp-240, Glu-269, Arg-302, Lys-319, His-322, and Glu-325) in the lactose permease. Neutral mutations were made involving five ion pairs that had not been previously studied. Double mutants, R302L/E325Q and D240N/H322Q, had moderate levels of downhill [(14)C]-lactose transport. Mutants in which only one of these six residues was left unchanged (pentuple mutants) were also made. A Pent269(-) mutant (in which only Glu-269 remains) catalyzed a moderate level of downhill lactose transport. Pent240(-) and Pent 322(+) also showed low levels of downhill lactose transport. Additionally, a Pent240(-) mutant exhibited proton transport upon addition of melibiose, but not lactose. This striking result demonstrates that neutralization of up to five residues of the lactose permease does not abolish proton transport. A mutant with neutral replacements at six ionic residues (hextuple mutant) had low levels of downhill lactose transport, but no uphill accumulation or proton transport. Since none of the mutants in this study catalyzes active accumulation of lactose, this is consistent with other reports that have shown that each residue is essential for proper coupling. Nevertheless, none of the six ionizable residues is individually required for substrate-induced proton cotransport. These results suggest that the H(+) binding domain may be elsewhere in the permease or that cation binding may involve a flexible network of charged residues.

Eosinophil activation and cysteinyl leukotriene production in infants with respiratory syncytial virus bronchiolitis.

BACKGROUND: It has been suggested that acute infantile bronchiolitis associated with respiratory syncytial virus (RSV) may share some pathogenic features with atopic asthma in that virus-specific IgE is produced and cysteinyl leukotrienes (cLTs) and eosinophil cationic protein (ECP) have been detected in airway secretions. ECP is a specific marker of eosinophil activation although leukotrienes can be released from a variety of cells including mast cells, eosinophils and monocytes. OBJECTIVE: To test the association between eosinophil activation and cysteinyl leukotriene production in the upper airway secretions of infants with RSV positive (RSV+ve) bronchiolitis. METHODS: Nasal lavage samples were performed in 78 infants (0.0-11.5 months) admitted to hospital with RSV+ve bronchiolitis soon after admission (0-48 h). Leukotriene C4 (LTC4) was assayed by enzyme immunoassay (EIA) and eosinophil cationic protein (ECP) by fluoroimmunoassay (FIA). RESULTS: LTC4 was detectable in 51 and ECP in 57 of 78 samples with a significant positive relationship between LTC4 and ECP (r=0.557, P<0.001). CONCLUSION: In the majority of our subjects with RSV+ve bronchiolitis ECP and LTC4 were detectable in upper airway secretions and were significantly associated with each other. In this clinical setting much of the detected LTC4 within upper airway secretions is likely to originate from the eosinophil, an observation that may have implications for clinical management and for delineation of the underlying mechanisms associated with this illness.

Importance of conserved acidic residues in mntH, the Nramp homolog of Escherichia coli.

A bioinformatic approach was used for the identification of residues that are conserved within the Nramp family of metal transporters. Site-directed mutagenesis was then carried out to change six conserved acidic residues (i.e., Asp-34, Glu-102, Asp-109, Glu-112, Glu-154, and Asp-238) in the E. coli Nramp homolog mntH. Of these six, five of them, Asp-34, Glu-102, Asp-109, Glu-112, and Asp-238 appear to be important for function since conservative substitutions at these sites result in a substantial loss of transport function. In addition, all of the residues within the signature sequence of the Nramp family, DPGN, were also mutated in this study. Each residue was changed to several different side chains, and of ten site-directed mutations made in this motif, only P35G showed any measurable level of (54)Mn(2+) uptake with a V(max) value of approximately 10% of wild-type and a slightly elevated K(m) value. Overall, the data are consistent with a model where helix breakers in the conserved DPGN motif in TMS-1 provide a binding pocket in which Asp-34, Asn-37, Asp-109, Glu-112 (and possibly other residues) are involved in the coordination of Mn(2+). Other residues such as Glu-102 and Asp238 may play a role in the release of Mn(2+) to the cytoplasm or may be involved in maintaining secondary structure.

Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis.

OBJECTIVE: To describe an in vivo model in the rat in which change in weight distribution is used as a measure of disease progression and efficacy of acetaminophen and two nonsteroidal anti-inflammatory drugs (NSAIDs) in a model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA). METHODS: Intra-articular injections of MIA and saline were administered to male Wistar rats (175-200 g) into the right and left knee joints, respectively. Changes in hind paw weight distribution between the right (osteoarthritic) and left (contralateral control) limbs were utilized as an index of joint discomfort. Acetaminophen and two archetypal, orally administered NSAIDs, naproxen and rofecoxib, were examined for their ability to decrease MIA-induced change in weight distribution. RESULTS: A concentration-dependent increase in change in hind paw weight distribution was noted after intra-articular injection of MIA. Both naproxen and rofecoxib demonstrated the capacity to significantly (P<0.05) decrease hind paw weight distribution in a dose-dependent fashion, indicating that the change in weight distribution associated with MIA injection is susceptible to pharmacological intervention. CONCLUSION: The determination of differences in hind paw weight distribution in the rat MIA model of OA is a technically straightforward, reproducible method that is predictive of the effects of anti-inflammatory and analgesic agents. This system may be useful for the discovery of novel pharmacologic agents in human OA.

The 'zero charge' partitioning behaviour of noble gases during mantle melting.

Noble-gas geochemistry is an important tool for understanding planetary processes from accretion to mantle dynamics and atmospheric formation. Central to much of the modelling of such processes is the crystal-melt partitioning of noble gases during mantle melting, magma ascent and near-surface degassing. Geochemists have traditionally considered the 'inert' noble gases to be extremely incompatible elements, with almost 100 per cent extraction efficiency from the solid phase during melting processes. Previously published experimental data on partitioning between crystalline silicates and melts has, however, suggested that noble gases approach compatible behaviour, and a significant proportion should therefore remain in the mantle during melt extraction. Here we present experimental data to show that noble gases are more incompatible than previously demonstrated, but not necessarily to the extent assumed or required by geochemical models. Independent atomistic computer simulations indicate that noble gases can be considered as species of 'zero charge' incorporated at crystal lattice sites. Together with the lattice strain model, this provides a theoretical framework with which to model noble-gas geochemistry as a function of residual mantle mineralogy.