Influence of the first wave of COVID-19 on asthma inhaler prescriptions.

In the beginning of the COVID-19 pandemic, there were major concerns regarding the huge demand for asthma inhalers. Using the primary-care medical records for 614,700 asthma patients between January and June 2020, we found that there was a substantial increase in inhalers solely in March 2020. Patients significantly associated with receiving higher inhaled corticosteroid prescriptions were younger, of higher socioeconomic status, and had milder asthma.

Inadequate specialist care referrals for high-risk asthma patients in the UK: an adult population-based cohort 2006-2017.

OBJECTIVE: To improve asthma morbidity and mortality in the UK, national asthma guidelines recommend referral to \ specialist care for the following high-risk groups, after a hospital admission for asthma, ≥3 courses of oral corticosteroids (OCS) in 12 months, an incident high-dose inhaled corticosteroid (ICS) prescription or addition of a fourth asthma drug to a patient's maintenance regimen. We sought to assess the prevalence and temporal change of referrals to identify unmet needs. METHODS: We used UK electronic healthcare records, 2006-2017, to identify high-risk asthma patients managed within primary care. Referrals to respiratory clinics in secondary care were measured, within 3 months before or 6 months after, an incident ICS, third OCS in a year, or fourth asthma drug; or 12 months after a hospital admission for asthma. A nested case-control and conditional logistic regression was used to evaluate factors associated with receiving a referral. RESULTS: A total of 246,116 asthma patients were eligible. There was a slight increase in secondary care referrals from 2014 onwards but the percentage remained low with <20% in each high-risk group referred for specialist care. The factors in the past year that were most strongly associated with receiving a referral were a hospital admission or A&E visit for asthma, ≥3 OCS courses, ≥2 add-on drugs, or high-dose ICS prescription. CONCLUSIONS: The majority of high-risk asthma patients were not referred for specialist care, as recommended by national guidelines. Compared to other risk factors, those admitted to hospital were most likely to receive a referral.

Author Correction: Inhibition of casein kinase 1δ/εimproves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer's disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Inhibition of casein kinase 1δ/εimproves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer's disease.

Circadian rhythm disruption is one of the earliest biomarkers of Alzheimer's disease (AD), and there exists a bidirectional relationship by which dysfunctions in the circadian clock drive AD pathology and AD pathology drives circadian dysfunction. Casein kinase 1 (CK1) isoforms ε and δ, key circadian regulators, are significantly upregulated in AD and may contribute to AD pathogenesis. In the current studies, we have examined how inhibition of CK1ε/δ with PF-670462 (at 10 mg/kg, δ isoform selective, or 30 mg/kg, δ and ε selective) impacts regional Aß and circadian gene expression in 10-13 month old APP-PS1 mice and nontransgenic controls. We have also assessed circadian, cognitive, and affective behavioral correlates of these neural changes. At baseline, APP-PS1 mice showed a short period, as well as impaired cognitive performance in both prefrontal cortex and hippocampus-dependent tasks. Both doses of PF-670462 lengthened the period and improved affect, whereas only the higher dose improved cognition. Further, PF-670462 treatment produced a dose-dependent reduction in amyloid burden - overall Aß signal decreased in all three areas; in the prefrontal cortex and hippocampus, PF-670462 also reduced plaque size. Together, these findings support chronotherapy as a potential tool to improve behavior in AD.

Predicting COPD 1-year mortality using prognostic predictors routinely measured in primary care.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of mortality. Patients with advanced disease often have a poor quality of life, such that guidelines recommend providing palliative care in their last year of life. Uptake and use of palliative care in advanced COPD is low; difficulty in predicting 1-year mortality is thought to be a major contributing factor. METHODS: We identified two primary care COPD cohorts using UK electronic healthcare records (Clinical Practice Research Datalink). The first cohort was randomised equally into training and test sets. An external dataset was drawn from a second cohort. A risk model to predict mortality within 12 months was derived from the training set using backwards elimination Cox regression. The model was given the acronym BARC based on putative prognostic factors including body mass index and blood results (B), age (A), respiratory variables (airflow obstruction, exacerbations, smoking) (R) and comorbidities (C). The BARC index predictive performance was validated in the test set and external dataset by assessing calibration and discrimination. The observed and expected probabilities of death were assessed for increasing quartiles of mortality risk (very low risk, low risk, moderate risk, high risk). The BARC index was compared to the established index scores body mass index, obstructive, dyspnoea and exacerbations (BODEx), dyspnoea, obstruction, smoking and exacerbations (DOSE) and age, dyspnoea and obstruction (ADO). RESULTS: Fifty-four thousand nine hundred ninety patients were eligible from the first cohort and 4931 from the second cohort. Eighteen variables were included in the BARC, including age, airflow obstruction, body mass index, smoking, exacerbations and comorbidities. The risk model had acceptable predictive performance (test set: C-index = 0.79, 95% CI 0.78-0.81, D-statistic = 1.87, 95% CI 1.77-1.96, calibration slope = 0.95, 95% CI 0.9-0.99; external dataset: C-index = 0.67, 95% CI 0.65-0.7, D-statistic = 0.98, 95% CI 0.8-1.2, calibration slope = 0.54, 95% CI 0.45-0.64) and acceptable accuracy predicting the probability of death (probability of death in 1 year, n high-risk group, test set: expected = 0.31, observed = 0.30; external dataset: expected = 0.22, observed = 0.27). The BARC compared favourably to existing index scores that can also be applied without specialist respiratory variables (area under the curve: BARC = 0.78, 95% CI 0.76-0.79; BODEx = 0.48, 95% CI 0.45-0.51; DOSE = 0.60, 95% CI 0.57-0.61; ADO = 0.68, 95% CI 0.66-0.69, external dataset: BARC = 0.70, 95% CI 0.67-0.72; BODEx = 0.41, 95% CI 0.38-0.45; DOSE = 0.52, 95% CI 0.49-0.55; ADO = 0.57, 95% CI 0.54-0.60). CONCLUSION: The BARC index performed better than existing tools in predicting 1-year mortality. Critically, the risk score only requires routinely collected non-specialist information which, therefore, could help identify patients seen in primary care that may benefit from palliative care.

ET-1 increases reactive oxygen species following hypoxia and high-salt diet in the mouse glomerulus.

AIM: This study was designed to determine whether ET-1 derived from endothelial cells contributes to oxidative stress in the glomerulus of mice subjected to a high-salt diet and/or hypoxia. METHODS: C57BL6/J control mice or vascular endothelial cell ET-1 knockout (VEET KO) mice were subjected to 3-h exposure to hypoxia (8% O2) and/or 2 weeks of high-salt diet (4% NaCl) prior to metabolic cage assessment of renal function and isolation of glomeruli for the determination of reactive oxygen species (ROS). RESULTS: In control mice, hypoxia significantly increased urinary protein excretion during the initial 24 h, but only in animals on a high-salt diet. Hypoxia increased glomerular ET-1 mRNA expression in control, but not in vascular endothelial cell ET-1 knockout (VEET KO) mice. Under normoxic conditions, mice on a high-salt diet had approx. 150% higher glomerular ET-1 mRNA expression compared with a normal-salt diet (P < 0.05). High-salt diet administration significantly increased glomerular ROS production in flox control, but not in glomeruli isolated from VEET KO mice. In C57BL6/J mice, the ETA receptor-selective antagonist, ABT-627, significantly attenuated the increase in glomerular ROS production produced by high-salt diet. In addition, chronic infusion of C57BL6/J mice with a subpressor dose of ET-1 (osmotic pumps) significantly increased the levels of glomerular ROS that were prevented by ETA antagonist treatment. CONCLUSION: These data suggest that both hypoxia and a high-salt diet increase glomerular ROS production via endothelial-derived ET-1-ETA receptor activation and provide a potential mechanism for ET-1-induced nephropathy.

Behavioral assessment of visual deficits in the taiep mutant.

Taiep (tremor, ataxia, immobility, epilepsy, paralysis) mutants show a significant increase in myelin thickness from 10 to 30 days of age but then demonstrate a decrease in myelin thickness from 1 to 6 months. The severity of the demyelination in the optic nerve suggests that visual deficits may exist in the taiep mutants. Animals were trained on a discrimination task, in which responses to a light stimulus (the SD period) were reinforced on a fixed ratio (FR)-1 schedule, and responses in the absence of the light stimulus (the SΔ period) were not reinforced. Following training, the light intensity presented during the SD period was gradually reduced between sessions until -6.0 candela/m2 was reached. Both groups of animals - taiep mutants and control Sprague Dawley rats - successfully recognized and responded in the presence of the stimulus near perfectly by the final day of training, suggesting that taiep mutants demonstrated normal learning, at least under this paradigm. Despite the severe demyelination of the taiep optic nerve, no visual deficits were detected as both groups of animals performed similarly as the light intensity decreased. Though the myelin loss of the optic nerve may have negatively affected signal transduction, this did not result in an increase in visual threshold.

Preliminary pharmacokinetics and cardiovascular effects of fenoldopam continuous rate infusion in six healthy dogs.

Fenoldopam is a selective dopamine-1 receptor agonist that causes peripheral arterial vasodilation, increased renal blood flow, and diuresis. Enthusiasm exists for the use of fenoldopam in nonpolyuric kidney injury in dogs, although pharmacokinetic data are lacking. The purpose of this study was to collect basic pharmacokinetic and hemodynamic effect data for fenoldopam when administered to healthy awake dogs. Six healthy, awake beagles were given a 180-min fenoldopam constant rate infusion at 0.8 µg/kg per minute followed by a 120-min washout period. Citrated blood was collected during and after infusion for the measurement of plasma fenoldopam concentration by HPLC with mass spectrometry. Heart rate and indirect systolic blood pressure were concurrently measured. Mean ± SD, steady-state plasma fenoldopam concentrations of 20 ± 17 ng/mL were achieved within 10 min of starting the infusion. Area under the plasma concentration-time curve was 3678 ± 3030 ng/mL · min, and plasma clearance was 66 ± 43 mL/min per kg. Elimination was rapidly achieved in all dogs. Heart rate and systolic blood pressure were unaffected by the fenoldopam infusion. Based on the results of this study, further evaluation of the effects of fenoldopam in dogs at differing doses and in dogs with clinical conditions such as acute nonpolyuric kidney injury is warranted.

Effect of age on kainate-induced seizure severity and cell death.

While the onset and extent of epilepsy increases in the aged population, the reasons for this increased incidence remain unexplored. The present study used two inbred strains of mice (C57BL/6J and FVB/NJ) to address the genetic control of age-dependent neurodegeneration by building upon previous experiments that have identified phenotypic differences in susceptibility to hippocampal seizure-induced cell death. We determined if seizure induction and seizure-induced cell death are affected differentially in young adult, mature, and aged male C57BL/6J and FVB/NJ mice administered the excitotoxin, kainic acid. Dose response testing was performed in three to four groups of male mice from each strain. Following kainate injections, mice were scored for seizure activity and brains from mice in each age group were processed for light microscopic histopathologic evaluation 7 days following kainate administration to evaluate the severity of seizure-induced brain damage. Irrespective of the dose of kainate administered or the age group examined, resistant strains of mice (C57BL/6J) continued to be resistant to seizure-induced cell death. In contrast, aged animals of the FVB/NJ strain were more vulnerable to the induction of behavioral seizures and associated neuropathology after systemic injection of kainic acid than young or middle-aged mice. Results from these studies suggest that the age-related increased susceptibility to the neurotoxic effects of seizure induction and seizure-induced injury is regulated in a strain-dependent manner, similar to previous observations in young adult mice.

Non-contingent positive and negative reinforcement schedules of superstitious behaviors.

The role of schedules of reinforcement on the development of superstitious conditioning was investigated in a college age population. Participants were randomly assigned to one of eight operant schedules and instructed to remove (escape), prevent and/or remove (avoidance and escape) or produce (positive) the appearance of a computer generated stimulus using a response pad. Results from the experiment indicate that concomitant (escape and avoidance) schedules of reinforcement are most effective in facilitating acquisition of superstitious behavior as measured by self-reports of participants.

An elderly lady with sudden blindness and a sore foot.

We report the case of an elderly woman presenting with group G streptococcal septicaemia associated with osteomyelitis and endophthalmitis.

Organic homojunction diodes with a high built-in potential: interpretation of the current-voltage characteristics by a generalized Einstein relation.

We realize p- and n-type doping of the organic semiconductor zinc-phthalocyanine using a novel strong organic donor. This allows us to demonstrate the first stable and reproducible organic p-n homojunctions. The diodes show very high built-in potentials, attractive, e.g., for organic solar cells. However, the diode characteristics cannot be described by the standard Shockley theory of the p-n junction since the ideality factor strongly increases with decreasing temperature. We show that this behavior can be explained by deviations from the Einstein relation for disordered materials.

Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction.

Many anxiety disorders, as well as major depressive disorder (MDD), are at least twice as prevalent in women as in men, but the neurobiological basis of this discrepancy has not been well studied. MDD is often precipitated by exposure to uncontrollable stress, and is frequently characterized by abnormal or disrupted prefrontal cortex (PFC) function. In animals, exposure to stress has been shown to cause PFC dysfunction, but sex differences in this effect have not been investigated. The present study tested male and female rats on a PFC-dependent working memory task after administration of FG7142, a benzodiazepine inverse agonist that activates stress systems in the brain. Female rats were impaired by lower doses than males during proestrus (high estrogen), but not during estrus (low estrogen). Similarly, ovariectomized females showed increased stress sensitivity only after estrogen replacement. These results suggest that estrogen amplifies the stress response in PFC, which may increase susceptibility to stress-related disorders.

The effect of anticholinesterases on personality changes in Alzheimer's disease.

Anticholinesterases are known to be effective against cognitive and non-cognitive symptoms of Alzheimer's disease (AD) but their effect on the personality changes in the disease is not known. This study examines the effect of anticholinesterase treatment on personality changes in AD. It involved the carers of patients with mild to moderate AD who were currently receiving anticholinesterases in south Manchester. The personality change was measured using the Brooks and McKinlay Personality Inventory. The carers were asked to complete the inventory for each of three periods in the patients' lives: before the onset of AD, after the diagnosis of AD but before starting anticholinesterases, and currently on anticholinesterases. Fifty-eight carers participated in the study. Personality became more negative (total score on the personality inventory became less) following the onset of AD (p < 0.001). Following anticholinesterase treatment, the total score on the personality inventory remained the same or increased in 23 (39%) patients. Scores on individual personality traits remained the same or increased in the majority of patients. In approximately one fifth of the patients, the traits 'does things himself', 'happy', 'calm' and 'cautious' showed improvement on anticholinesterases. The study confirms that personality changes are almost universal and negative in AD and suggests that anticholinesterases may have a positive effect. Further double blind prospective studies are needed to understand natural progression of personality changes in AD and to validate the findings of this study.

Behavioral effects of chronic melatonin and pregnenolone injections in a myelin mutant rat (taiep).

The taiep (tremor, ataxia, immobility, epilepsy, and paralysis) myelin mutant displays a number of locomotor deficits. Taiep rat gait is characterized by shorter stride and step lengths as well as by larger stride widths. Thirty-day-old taiep mutants were placed under a regimen of daily hormone injections for 60 days. Animals in Condition 1 received melatonin, those in Condition 2 received pregnenolone sulfate, and those in a third control condition received injections of saline. Following the injections, each taiep mutant's gait was analyzed. The animals that received melatonin and pregnenolone displayed significantly larger stride and step lengths than did the controls. In addition, the animals that received hormones displayed shorter stride widths than did the controls. These experimental effects are consistent with a normalization of gait. Possible cellular mechanisms of this behavioral effect are discussed.

Tervalent conducting polymers with tailor-made work functions: preparation, characterization, and applications as cathodes in electroluminescent devices.

A series of conducting polymers have been prepared through thermal polymerization of transition-metal diimine complexes. The as-polymerized material is electrochemically converted into its formally zerovalent form. Due to the proximity of the half-wave potentials of the formal 1+/0 and 0/1- couples, there is substantial disproportionation of the redox sites at room temperature, resulting in a conductive tervalent mixed-valent material. The redox processes that give rise to this mixed-valent material are predominantly ligand-based, and therefore are highly sensitive to substitution on the ligand periphery. Solution redox chemistry of the monomer can be used to accurately predict the work function of the corresponding zerovalent conducting polymer, which has been verified by ultraviolet photoelectron spectroscopy. Many of these materials have especially low work functions (<3.6 eV) making them appropriate materials to use as cathode materials in organic light-emitting devices (OLEDs). Working examples of tris(8-hydroxyquinoline)aluminum(III)-based OLEDs have been fabricated using one of these polymers as a cathode.

Locomotor analysis of the taiep rat.

Locomotor activity (tremor, ataxia, immobility, epilepsy, and paralysis) in the taiep rat, which suffers from a myelin deficient disorder, has not been previously documented. This study used walking track analysis of footprints to analyze locomotor activity in the taiep rat in comparison to normal, age-matched controls. The results confirmed differences between normal and taiep rats in terms of stride length, step length, and stride width. In addition, we found significant interactions between age and condition for stride and step length. The results suggest that locomotor analysis is a sensitive indicator of myelin deficiency. The results are discussed in terms of the underlying myelin deficiency and possible treatment regimens.

The splay angle: A new measure for assessing neuromuscular dysfunction in rats.

This report describes a new method, the splay angle measures, to determine neuromuscular dysfunction. Splay angles are measured from a standard splay test and define hind limb orientation quantified, in degrees, by the paw strike of the hind limbs. We used mutant rats, presenting with a chronic central nervous system demyelinating disease, characterized by tremor, ataxia, immobility, epilepsy, and paralysis (taiep). Significant differences between taiep (n = 12) and normal control rats (n = 10) were found for Linear Splay, AngleLeft, AngleRight, and AngleBoth. These results suggest that the splay angles are a sensitive measure of hind limb orientation and may reflect an underlying pathology.