Over-prescription of short-acting β2-agonists is associated with poor asthma outcomes: results from the African cohort of the SABINA III study

Background The extent of short-acting β2-agonist (SABA) overuse in Africa remains poorly documented. As part of the SABA use IN Asthma (SABINA) III study, we assessed SABA prescriptions/clinical outcomes in 3 African countries. Methods Data on disease characteristics/asthma treatments were collected from patients (≥12 years) using electronic case report forms. Patients were classified by investigator-defined asthma severity (guided by the 2017 Global Initiative for Asthma) and practice type (primary/specialist care). Multivariable regression models analyzed associations between SABA prescriptions and outcomes. Results Data from 1778 patients (mean age, 43.7 years) were analyzed. Most patients were female (62.4%) and had moderate-to-severe asthma (63.3%), with 57.1 and 42.9% of patients treated in specialist and primary care, respectively. Asthma was partly controlled/uncontrolled in 66.2% of patients, with 57.9% experiencing ≥1 severe exacerbation in the previous 12 months. Overall, 46.5% of patients were prescribed ≥3 SABA canisters in the preceding 12 months (over-prescription); 26.2% were prescribed ≥10 canisters. SABAs were purchased over-the-counter by 32.6% of patients, of whom 79.3% had received SABA prescriptions; 71.9% and 40.1% for ≥3 and ≥10 canisters, respectively. Higher SABA prescriptions (vs. 1–2 canisters) were associated with increased incidence rate of severe exacerbations and lower odds of having at least partly controlled asthma (except 3–5 canisters). Conclusions Findings from this African cohort of the SABINA III study indicate that SABA over-prescription and SABA over-the-counter purchase are common and associated with poor asthma-related outcomes. This highlights the need for healthcare providers/policymakers to align clinical practices with the latest treatment recommendations

Concert recording 2017-04-23b

[Track 1]. Slowing down. I. Rotations in an emergency [Track 2]. II. Under the city [Track 3]. III. Forfeit [Track 4]. IV. Something comfortable to fall into / Jeremiah Flannery

Climatic history of the northeastern United States during the past 3000 years

Many ecosystem processes that influence Earth system feedbacks – vegetation growth, water and nutrient cycling, disturbance regimes – are strongly influenced by multidecadal- to millennial-scale climate variations that cannot be directly observed. Paleoclimate records provide information about these variations, forming the basis of our understanding and modeling of them. Fossil pollen records are abundant in the NE US, but cannot simultaneously provide information about paleoclimate and past vegetation in a modeling context because this leads to circular logic. If pollen data are used to constrain past vegetation changes, then the remaining paleoclimate archives in the northeastern US (NE US) are quite limited. Nonetheless, a growing number of diverse reconstructions have been developed but have not yet been examined together. Here we conduct a systematic review, assessment, and comparison of paleotemperature and paleohydrological proxies from the NE US for the last 3000 years. Regional temperature reconstructions (primarily summer) show a long-term cooling trend (1000 BCE–1700 CE) consistent with hemispheric-scale reconstructions, while hydroclimate data show gradually wetter conditions through the present day. Multiple proxies suggest that a prolonged, widespread drought occurred between 550 and 750 CE. Dry conditions are also evident during the Medieval Climate Anomaly, which was warmer and drier than the Little Ice Age and drier than today. There is some evidence for an acceleration of the longer-term wetting trend in the NE US during the past century; coupled with an abrupt shift from decreasing to increasing temperatures in the past century, these changes could have wide-ranging implications for species distributions, ecosystem dynamics, and extreme weather events. More work is needed to gather paleoclimate data in the NE US to make inter-proxy comparisons and to improve estimates of uncertainty in reconstructions

Type I interferon-mediated monogenic autoinflammation:The type I interferonopathies, a conceptual overview

International audienc

The SARS-CoV-2 Alpha variant was associated with increased clinical severity of COVID-19 in Scotland: A genomics-based retrospective cohort analysis

Objectives The SARS-CoV-2 Alpha variant was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between Alpha variant infection and increased hospitalisation and 28-day mortality. However, none have addressed the impact on maximum severity of illness in the general population classified by the level of respiratory support required, or death. We aimed to do this. Methods In this retrospective multi-centre clinical cohort sub-study of the COG-UK consortium, 1475 samples from Scottish hospitalised and community cases collected between 1st November 2020 and 30th January 2021 were sequenced. We matched sequence data to clinical outcomes as the Alpha variant became dominant in Scotland and modelled the association between Alpha variant infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no respiratory support, 2. supplemental oxygen, 3. ventilation and 4. death. Results Our cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (Alpha variant versus pre-Alpha variants). Conclusions The Alpha variant was associated with more severe clinical disease in the Scottish population than co-circulating lineages

Comparative, Topographically-Based Evaluation of Behavioural Phenotype and Specification of D1-Like:D2 Interactions in a Line of Incipient Congenic Mice with D2 Dopamine Receptor "Knockout"

Phenotypes were assessed topographically in mice lacking functional D2 dopamine receptors [‘knockouts’], using an ethologically based approach to assess all behaviours in the natural repertoire. D2-null mice evidenced an ethogram characterised initially by modest reductions in locomotion and shifts in rearing topographies. Subsequently, topographies of behaviour habituated similarly for wildtypes and ‘knockouts’. Following challenge with the D2-like agonist RU 24213, both inhibition of rearing at a lower dose and induction of stereotyped sniffing and ponderous locomotion at higher doses were essentially absent in D2-null mice. Following challenge with the D1-like agonist A 68930, vacuous chewing was released in D2-null mice. This topographical approach to phenotypic characterisation implicates: (i) the D2 receptor in these D2-like agonist effects and in oppositional D1-like: D2-like interactions; and (ii) the operation of material compensatory processes consequent to the developmental absence of D2 receptors which are able to maintain ethological function under tonic, ‘naturalistic’ conditions but not under ‘phasic’ challenge.Fil: Clifford, Jeremiah J.. Royal College of Surgeons; Irlanda. Tralee General Hospital; IrlandaFil: Kinsella, Anthony. Dublin Institute of Technology; IrlandaFil: Tighe, Orna. Royal College of Surgeons; IrlandaFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Grandy, David K.. Oregon Health Science University; Estados UnidosFil: Low, Malcolm J.. Oregon Health Science University; Estados UnidosFil: Croke, David T.. Royal College of Surgeons; IrlandaFil: Waddington, John L.. Royal College of Surgeons; Irland

Phenotypic characterization of spatial cognition and social behavior in mice with 'knockout' of the schizophrenia risk gene neuregulin 1.

Neuregulin-1 (NRG1) has been identified as a candidate susceptibility gene for schizophrenia. In the present study the functional role of the NRG1 gene, as it relates to cognitive and social processes known to be disrupted in schizophrenia, was assessed in mice with heterozygous deletion of transmembrane (TM)-domain NRG1 in comparison with wildtypes (WT). Social affiliative behavior was assessed using the sociability and preference for social novelty paradigm, in terms of time spent in: (i) a chamber containing an unfamiliar conspecific vs. an empty chamber (sociability), or (ii) a chamber containing an unfamiliar conspecific vs. a chamber containing a familiar conspecific (preference for social novelty). Social dominance and aggressive behavior were examined in the resident-intruder paradigm. Spatial learning and memory were assessed using the Barnes maze paradigm, while spatial working memory was measured using the continuous variant of the spontaneous alternation task. Barnes maze data revealed intact spatial learning in NRG1 mutants, with elevated baseline latency to enter the escape hole in male NRG1 mutants reflecting an increase in activity level. Similarly, although a greater number of overall arm entries were found, spontaneous alternation was unaffected in NRG1 mice. Social affiliation data revealed NRG1 mutants to evidence a specific loss of WT preference for spending time with an unfamiliar as opposed to a familiar conspecific. This suggests that NRG1 mutants show a selective impairment in response to social novelty. While spatial learning and working memory processes appear intact, heterozygous deletion of TM-domain NRG1 was associated with disruption to social novelty behavior. These data inform at a novel phenotypic level on the functional role of this gene in the context of its association with risk for schizophrenia

Comparative phenotypic resolution of spontaneous, D2-like and D1-like agonist-induced orofacial movement topographies in congenic mutants with dopamine D2 vs. D3 receptor "knockout"

Using a novel system, the role of D2-like dopamine receptors in distinct topographies of orofacial movement was assessed in mutant mice with congenic D2 vs. D3 receptor knockout, and compared with findings in D1A mutants. Under spontaneous conditions, D2 mutants evidenced increased vertical jaw movements and unaltered horizontal jaw movements, with reductions in tongue protrusions and incisor chattering; in D3 mutants, only incisor chattering was reduced. Given previous evidence that D1A mutants show reduced horizontal but not vertical jaw movements, this indicates that apparent oppositional D1-like:D2-like interactions in the regulation of composited jaw movements may in fact reflect the independent actions of D2 receptors to inhibit vertical jaw movements and of D1A receptors to facilitate horizontal jaw movements. Effects of the D2-like agonist RU 24213 to exert greater reduction in horizontal than in vertical jaw movements were not altered prominently in either D2 or D3 mutants. The D1-like agonists A 68930 and SK&F 83959 induced vertical jaw movements, tongue protrusions, and incisor chattering; induction of tongue protrusions by A 68930 was reduced in D2 mutants. D2 receptors exert topographically specific regulation of orofacial movements in a manner distinct from their D1A counterparts, while D3 receptors exert only minor regulation of such movements.Fil: Tomiyama, Katsunori. Royal College of Surgeons in Ireland; Irlanda. Nihon University School of Dentistry; JapónFil: Mcnamara, Fergal N.. Royal College of Surgeons in Ireland; IrlandaFil: Clifford, Jeremiah J.. Royal College of Surgeons in Ireland; IrlandaFil: Kinsella, Anthony. Dublin Institute of Technology; IrlandaFil: Drago, John. Monash Medical Centre; AustraliaFil: Fuchs, Sara. Weizmann Institute of Science; IsraelFil: Grandy, David K.. Oregon Health Sciences University; Estados UnidosFil: Low, Malcolm J.. Oregon Health Sciences University; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Tighe, Orna. Royal College of Surgeons in Ireland; IrlandaFil: Croke, David T.. Royal College of Surgeons in Ireland; IrlandaFil: Koshikawa, Noriaki. Nihon University School of Dentistry; JapónFil: Waddington, John L.. Royal College of Surgeons in Ireland; Irland

Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice.

Catechol-O-methyltransferase (COMT) inactivates dopamine in prefrontal cortex and is associated clinically with a schizophrenia endophenotype. Using an ethologically based approach, the phenotype of mice with heterozygous COMT deletion was characterised by decreased rearing with increased sifting and chewing. Heterozygous COMT deletion is associated with a distinctive phenotype. This differs from that which we have reported previously for heterozygous deletion of the schizophrenia risk gene neuregulin-1