Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.Swedish Research Council et al.Manuscrip

Real-world experience of nintedanib for progressive fibrosing interstitial lung disease in the UK

Background Nintedanib slows progression of lung function decline in patients with progressive fibrosing (PF) interstitial lung disease (ILD) and was recommended for this indication within the United Kingdom (UK) National Health Service in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date, there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting.Methods 26 UK centres were invited to take part in a national service evaluation between 17 November 2021 and 30 September 2022. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability were collected via electronic survey.Results 24 UK prescribing centres responded to the service evaluation invitation. Between 17 November 2021 and 30 September 2022, 1120 patients received a multidisciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298 out of 1120, 26.6%), connective tissue disease associated ILD (197 out of 1120, 17.6%), rheumatoid arthritis associated ILD (180 out of 1120, 16.0%), idiopathic nonspecific interstitial pneumonia (125 out of 1120, 11.1%) and unclassifiable ILD (100 out of 1120, 8.9%). Of these, 54.4% (609 out of 1120) were receiving concomitant corticosteroids, 355 (31.7%) out of 1120 were receiving concomitant mycophenolate mofetil and 340 (30.3%) out of 1120 were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD.Conclusion We have demonstrated the use of nintedanib for the treatment of PF-ILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD has demonstrated acceptable tolerability in a real-world setting

Hearing and dementia

Hearing deficits associated with cognitive impairment have attracted much recent interest, motivated by emerging evidence that impaired hearing is a risk factor for cognitive decline. However, dementia and hearing impairment present immense challenges in their own right, and their intersection in the auditory brain remains poorly understood and difficult to assess. Here, we outline a clinically oriented, symptom-based approach to the assessment of hearing in dementias, informed by recent progress in the clinical auditory neuroscience of these diseases. We consider the significance and interpretation of hearing loss and symptoms that point to a disorder of auditory cognition in patients with dementia. We identify key auditory characteristics of some important dementias and conclude with a bedside approach to assessing and managing auditory dysfunction in dementia

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

A prenylated dsRNA sensor protects against severe COVID-19

Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that a common splice-acceptor SNP (Rs10774671) governs whether people express prenylated OAS1 isoforms that are membrane-associated and sense specific regions of SARS-CoV-2 RNAs, or only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response

Leaf wax n-alkane distributions in arid zone South African flora: Environmental controls, chemotaxonomy and palaeoecological implications

International audienceThe environmental controls on leaf wax n-alkane distributions and associated interpretation of such distributions in geological archives have long remained rather enigmatic. Studies of contemporary vegetation often conflate changing environmental conditions and species differences between biomes, making it difficult to assess the extent to which variation is driven by plant adaptation to prevailing environmental conditions and/or more fixed chemotaxonomic patterns. We present a case study of arid and semi-arid regions of South Africa that considers these issues. We anticipate that such conditions may impart strong controls upon leaf wax synthesis. Leaf wax n-alkane data from 215 plants and 93 soils from the Succulent Karoo and Fynbos biomes of South Africa revealed yield and distributions to be highly variable. While many plants exhibited concentrations comparable with previous reports, several succulent plants produced n-alkane yield up to 100Â the modal n-alkane concentration for their biome. The data demonstrate that, on average, leaf wax n-alkane distributions in the Succulent Karoo are different from those of the Fynbos biome, with the former associated with longer maximum chain length, less dispersed distributions and stronger odd numbered chain length preference. The patterns were closely mirrored in the soils. Average chain length was weakly correlated with climate and this is interpreted to be a function of multiple factors. We hypothesise that a key control is the shifting proportion of plant functional type between biomes, with a greater abundance of succulent growth forms in the more arid Succulent Karoo (which tended to produce longer and less dispersed n-alkane chain length distributions), differentiating this biome from the Fynbos, in which woody shrubs are more dominant. Inter-biome variability was also apparent, with some same taxonomic or functional groups common to both biomes tending to produce longer chain length n-alkane distributions under more arid conditions. There was, however, considerable individual plant variability and we observed both insensitivity to environmental conditions (i.e. consistent n-alkane distributions) and marked variability in chain length distributions. A key finding is the high yield of n-alkanes from multiple succulent plants, many of which use the CAM photosynthetic pathway. Compound specific d 13 C/dD analyses (e.g. estimates of C 3 and C 4 biomass) for regions with potential succulent plant contributions should therefore be carried out cautiously

Holocene sea level and environmental change on the west coast of South Africa: evidence from plant biomarkers, stable isotopes and pollen

We present an 8,000-year biomarker and stable carbon isotope record from the Verlorenvlei Estuary, South Africa. We assessed how leaf wax lipids, insoluble macromolecular organic matter, bulk C/N data and compound-specific stable carbon isotopes were linked to the site’s palynological record and to evidence for regional sea level and environmental change. Down-core trends in bulk δ13C are closely coupled to trends in pollen types from saline-tolerant taxa. These trends are mirrored by variations in the incorporation of reduced sulphur into macromolecular organic matter. This process, quantified with the thiophene ratio, is closely associated with periods of higher sea level 8,000-4,300 cal yr BP. We propose the thiophene ratio is a proxy for relative marine influence within (peri) estuarine sediments. All measured variables indicate differences between early-middle Holocene (8,000-4,300 cal BP) and late Holocene conditions at Verlorenvlei. The former period was more saline and preserves more labile macromolecular organic matter. Marine influence declined after 4,300 cal yr BP, and although the abundance of short-chain-length n-alkanes suggests continued presence of wetland flora until 2,500 cal yr BP, organic matter preservation became poorer and a drying trend was inferred, most notably for the interval 2,500-900 cal BP. Increasing freshwater inundation is apparent during the last 700 cal years, consistent with several records from this region. Leaf wax n-alkane distributions are largely uncorrelated with bulk organic matter variables, with the exception of the abundance of C31 and C33 n-alkanes, which are negatively correlated with δ13CTOC. Furthermore, C31-C33 n-alkane δ13C values are uncorrelated with C23-C29 δ13C and δ13CTOC. They are also higher than our newly measured terrestrial (C3) vegetation C29 and C31 end-member values of -35 ± 2 and -34 ± 1‰, respectively. These patterns are best explained by a dominant contribution of local riparian vegetation to the C23-C29 n-alkanes, but time-varying contributions of non-local leaf waxes to the C31-C33 signals. This renders inferences concerning regional environmental change from long-chain leaf waxes potentially challenging in this setting

Beta-2 adrenergic receptor agonism alters astrocyte phagocytic activity and has potential applications to psychiatric disease

Schizophrenia is a debilitating condition necessitating more efficacious therapies. Previous studies suggested that schizophrenia development is associated with aberrant synaptic pruning by glial cells. We pursued an interdisciplinary approach to understand whether therapeutic reduction in glial cell-specifically astrocytic-phagocytosis might benefit neuropsychiatric patients. We discovered that beta-2 adrenergic receptor (ADRB2) agonists reduced phagocytosis using a high-throughput, phenotypic screen of over 3200 compounds in primary human fetal astrocytes. We used protein interaction pathways analysis to associate ADRB2, to schizophrenia and endocytosis. We demonstrated that patients with a pediatric exposure to salmeterol, an ADRB2 agonist, had reduced in-patient psychiatry visits using a novel observational study in the electronic health record. We used a mouse model of inflammatory neurodegenerative disease and measured changes in proteins associated with endocytosis and vesicle-mediated transport after ADRB2 agonism. These results provide substantial rationale for clinical consideration of ADRB2 agonists as possible therapies for patients with schizophrenia