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35th European Cystic Fibrosis ConferenceThe Convention Centre, Dublin, Ireland, 6-9 June 2012More than 2400 delegates attended the 35th European Cystic Fibrosis Conference held in Dublin between 6 and 9 June 2012. More than 525 abstracts were presented at the conference. There were 30 symposia with four speakers at each, in addition to numerous workshops where researchers had the opportunity to present their work into scientific, clinical and psychological aspects of cystic fibrosis care. Keynote speakers provided state of the art lectures in two plenary sessions. This report highlights two important areas in the field of molecular genetics and the need for new and validated clinical trial end points.

Genome-Wide Association Studies (GWAS) implicate SPI1 (PU.1) as a risk factor for late-onset Alzheimer's Disease (LOAD). Within the brain, SPI1 encodes a microglia-specific transcription factor, necessary for microglial proliferation and activation. SPI1 rs1377416 has been identified as a non-coding GWAS risk variant for AD. We have developed a novel mouse model with the SPI1 rs1377416 variant to explore its impacts on AD pathogenesis. By using CRISPR/Cas9, we have generated SPI1*rs1377416 mice that carry a non-coding mutation corresponding to the rs1377416 SNP found in human SPI1. We crossed the SPI1 mice with the 5xFAD mouse model of AD and aged them to 4 and 12 months of age. Coronal brain sections were then obtained and immunolabeled with several markers to visualize amyloid plaques, glial cells and assess axonal and neuritic damage. Confocal images were then obtained and quantified in subiculum and cortex. We found an age-related increase in dense core plaque number and size in the subiculum of 5xFAD;SPI1 mice. Microglial volume as well as astrocytic activation were reduced in 5xFAD;SPI1 compared to 5xFAD mice in both brain areas at 12 months. Correspondingly, neuritic dystrophy and axonal damage were also diminished. Significant sex difference was observed in different analyses with males being affected less than females (with the exception of plaque deposition), and mainly detected in subiculum. Our results indicate that the rs1377416 variant of SPI1 induces an age-dependent increase in amyloid deposition in the 5xFAD model of AD. Moreover, this SPI1 variant exerts a protective effect by suppressing astrocytic response and preventing neuritic and axonal damage. There is a strong sex difference observed between males and females when the variant is present and requires further investigation.

Background Genome‐Wide Association Studies (GWAS) implicate SPI1 (PU.1) as a risk factor for late‐onset Alzheimer’s Disease (LOAD). Within the brain, SPI1 encodes a microglia‐specific transcription factor, necessary for microglial proliferation and activation. SPI1 rs1377416 has been identified as a non‐coding GWAS risk variant for AD. We have developed a novel mouse model with the SPI1 rs1377416 variant to explore its impacts on AD pathogenesis. Method By using CRISPR/Cas9, we have generated SPI1*rs1377416 mice that carry a non‐coding mutation corresponding to the rs1377416 SNP found in human SPI1. We crossed the SPI1 mice with the 5xFAD mouse model of AD and aged them to 4 and 12 months of age. Coronal brain sections were then obtained and immunolabeled with several markers to visualize amyloid plaques, glial cells and assess axonal and neuritic damage. Confocal images were then obtained and quantified in subiculum and cortex. Result We found an age‐related increase in dense core plaque number and size in the subiculum of 5xFAD;SPI1 mice. Microglial volume as well as astrocytic activation were reduced in 5xFAD;SPI1 compared to 5xFAD mice in both brain areas at 12 months. Correspondingly, neuritic dystrophy and axonal damage were also diminished. Significant sex difference was observed in different analyses with males being affected less than females (with the exception of plaque deposition), and mainly detected in subiculum. Conclusion Our results indicate that the rs1377416 variant of SPI1 induces an age‐dependent increase in amyloid deposition in the 5xFAD model of AD. Moreover, this SPI1 variant exerts a protective effect by suppressing astrocytic response and preventing neuritic and axonal damage. There is a strong sex difference observed between males and females when the variant is present and requires further investigation.

Background In several large genome‐wide association studies (GWAS), genetic polymorphisms of Abi3 have been identified as a risk factor for late‐onset Alzheimer’s Disease (LOAD). ABI3 along with ABI1 and ABI2, regulate the formation of the WAVE complex which in turn, regulates actin dynamics. ABI3 is highly expressed in microglia in the brain, however, the function of ABI3 in microglia is relatively unknown. In recent studies knock‐out of ABI3 has been shown to exacerbate amyloid beta (Aβ) pathology and associated inflammation. To date, there have been no studies on variant specific effects on amyloid beta pathology. Methods To study the effects of ABI3 on the development of Alzheimer’s disease (AD) relevant pathologies we introduced an equivalent coding sequence change that has been identified as a risk variant for LOAD (S212F) into the C57BL/6 mouse genome using CRISPR/Cas9 (S209F). We set out to characterize the Abi3S209F variant and investigate its impact on AD pathology when crossed with 5xFAD transgenic mice, generating four distinct groups: WT, Abi3S209F homozygous, 5xFAD, and 5xFAD/Abi3S209F homozygous. Characterization was performed using histological staining and biochemical approaches at 4‐, 12‐ and 18‐months of age. Results 5xFAD/Abi3S209F mice displayed an age‐related decrease in dense core‐Aβ plaque burden, characterized by reduced Thioflavin‐S staining, accompanied by changes in fibrillar Aβ (OC) staining, in confocal images of both subiculum and visual cortical regions of 5xFAD/Abi3S209F mice compared to 5xFAD mice. Broadly, microglial numbers mimic plaque load, however by 18‐months of age 5xFAD/Abi3S209F mice display dramatic reductions in IBA1+ microglia number – to levels comparable to WT/Abi3S209F homozygous mice, suggesting a general loss of plaque associated microglia. By 12 months of age, Abi3S209F homozygous and 5xFAD/ Abi3S209F mice displayed increased synaptic density, independent of pathology in visual cortex, subiculum and CA1 regions. Conclusions Together, these results characterize the effects of the Abi3S209F missense mutation on 5xFAD‐mediated pathology, specifically in Aβ plaque development, glial morphology, and synapses. Our data suggests that this mutation may affect microglia dynamics in an age‐dependent manner and may result in dysfunctional microglia at later stages of disease.

In several large genome-wide association studies (GWAS), genetic polymorphisms of Abi3 have been identified as a risk factor for late-onset Alzheimer's Disease (LOAD). ABI3 along with ABI1 and ABI2, regulate the formation of the WAVE complex which in turn, regulates actin dynamics. ABI3 is highly expressed in microglia in the brain, however, the function of ABI3 in microglia is relatively unknown. In recent studies knock-out of ABI3 has been shown to exacerbate amyloid beta (Aβ) pathology and associated inflammation. To date, there have been no studies on variant specific effects on amyloid beta pathology. To study the effects of ABI3 on the development of Alzheimer's disease (AD) relevant pathologies we introduced an equivalent coding sequence change that has been identified as a risk variant for LOAD (S212F) into the C57BL/6 mouse genome using CRISPR/Cas9 (S209F). We set out to characterize the Abi3 variant and investigate its impact on AD pathology when crossed with 5xFAD transgenic mice, generating four distinct groups: WT, Abi3 homozygous, 5xFAD, and 5xFAD/Abi3 homozygous. Characterization was performed using histological staining and biochemical approaches at 4-, 12- and 18-months of age. 5xFAD/Abi3 mice displayed an age-related decrease in dense core-Aβ plaque burden, characterized by reduced Thioflavin-S staining, accompanied by changes in fibrillar Aβ (OC) staining, in confocal images of both subiculum and visual cortical regions of 5xFAD/Abi3 mice compared to 5xFAD mice. Broadly, microglial numbers mimic plaque load, however by 18-months of age 5xFAD/Abi3 mice display dramatic reductions in IBA1+ microglia number - to levels comparable to WT/Abi3 homozygous mice, suggesting a general loss of plaque associated microglia. By 12 months of age, Abi3 homozygous and 5xFAD/ Abi3 mice displayed increased synaptic density, independent of pathology in visual cortex, subiculum and CA1 regions. Together, these results characterize the effects of the Abi3 missense mutation on 5xFAD-mediated pathology, specifically in Aβ plaque development, glial morphology, and synapses. Our data suggests that this mutation may affect microglia dynamics in an age-dependent manner and may result in dysfunctional microglia at later stages of disease.

ObjectiveThe COVID-19 pandemic has transformed healthcare delivery in the USA, but there has been little empirical work describing the impact of these changes on clinicians. We conducted a study to address the following question: how has the pandemic impacted US clinicians’ professional roles and relationships?DesignInductive thematic analysis of semi-structured interviews.SettingClinical settings across the USA in April and May of 2020.ParticipantsClinicians with leadership and/or clinical roles during the COVID-19 pandemic.MeasuresEmergent themes related to professional roles and relationships.ResultsSixty-one clinicians participated in semi-structured interviews. Study participants were practising in 15 states across the USA, and the majority were White physicians from large academic centres. Three overlapping and inter-related themes emerged from qualitative analysis of interview transcripts: (1) disruption: boundaries between work and home life became blurred and professional identity and usual clinical roles were upended; (2) constructive adaptation: some clinicians were able to find new meaning in their work and described a spirit of collaboration, shared goals, open communication and mutual respect among colleagues; and (3) discord and estrangement: other clinicians felt alienated from their clinical roles and experienced demoralising work environments marked by division, value conflicts and mistrust.ConclusionsClinicians encountered marked disruption of their professional roles, identities and relationships during the pandemic to which they and their colleagues responded in a range of different ways. Some described a spirit of collaboration and camaraderie, while others felt alienated by their new roles and experienced work environments marked by division, value conflicts and mistrust. Our findings highlight the importance of effective teamwork and efforts to support clinician well-being during the COVID-19 pandemic.

The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. UK National Institute for Health and Care Research

Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. British Heart Foundation.

Background The serial interval is the period of time between the onset of symptoms in an infector and an infectee and is an important parameter which can impact on the estimation of the reproduction number. Whilst several parameters influencing infection transmission are expected to be consistent across populations, the serial interval can vary across and within populations over time. Therefore, local estimates are preferable for use in epidemiological models developed at a regional level. We used data collected as part of the national contact tracing process in Ireland to estimate the serial interval of SARS-CoV-2 infection in the Irish population, and to estimate the proportion of transmission events that occurred prior to the onset of symptoms. Results After data cleaning, the final dataset consisted of 471 infected close contacts from 471 primary cases. The median serial interval was 4 days, mean serial interval was 4.0 (95% confidence intervals 3.7, 4.3) days, whilst the 25th and 75th percentiles were 2 and 6 days respectively. We found that intervals were lower when the primary or secondary case were in the older age cohort (greater than 64 years). Simulating from an incubation period distribution from international literature, we estimated that 67% of transmission events had greater than 50% probability of occurring prior to the onset of symptoms in the infector. Conclusions Whilst our analysis was based on a large sample size, data were collected for the primary purpose of interrupting transmission chains. Similar to other studies estimating the serial interval, our analysis is restricted to transmission pairs where the infector is known with some degree of certainty. Such pairs may represent more intense contacts with infected individuals than might occur in the overall population. It is therefore possible that our analysis is biased towards shorter serial intervals than the overall population.