SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

Risk Factors for Retinal Detachment: A Case-Control Study

Objective:The aim of this study was to investigate risk factors for retinal detachment or tear (RD/T), and follow up two studies that found increased risk from work-related heavy lifting.Methods:We conducted a case-control study including 200 cases of RD/T and 415 controls. Participants completed a questionnaire covering general health, vision, and physical exertion. Multiple logistic regression and propensity score matching was used to control confounding and estimate independent effects.Results:RD/T risk was increased by one lifting measure: current regular lifting of more than 30lbs (&gt;13.6kg). In the population aged less than 65 years, the odds ratio comparing those with/without heavy lifting was 1.81, 95% confidence interval=1.08 to 3.04.Conclusion:Occupational heavy lifting may represent a risk factor for RD/T, but further research is needed in populations with frequent heavy physical exertion to more precisely quantify the risk

Aligning laboratory and field compaction practices for asphalt – the influence of compaction temperature on mechanical properties

The approach used to identify a compaction temperature in the laboratory, based on binder viscosity, provides a single compaction temperature whereas, on-site, a roller operates within a temperature window. The effect on the density and mechanical properties of rolling during a temperature window remains unclear. Consequently, asphalt concrete binder mixtures were compacted in different temperature windows in the laboratory using a Roller Sector Compactor, and the observed phenomena were then related to field study observations. The results show that while similar densities can be achieved in a broad range of temperature windows, other mechanical properties such as fracture energy may decline up to 30% if compacted outside the optimum temperature window. These results indicate that a compaction temperature window should form part of mix design and quality control. The paper proposes specifying a compaction window based on temperatures and the resulting mechanical properties rather than a single compaction temperature

Dinâmica do chumbo no lago do parque Ingá, Maringá, PR, Brasil

Este trabalho analisa a dinâmica do chumbo no lago do parque do Ingá, Maringá - PR. Mensalmente durante um ano foram coletadas amostras de água e sedimentos e o pH e temperatura medidos no ato da coleta. Nas amostras de água foi determinada a Demanda Química de Oxigênio (DQO) e a concentração total de Pb na água e sedimentos. A determinação da concentração Pb na água e sedimentos foi feita com a técnica da espectrometria da absorção atômica, modalidade chama. Os valores médios mensais encontrados, em intervalos e médias globais foram respectivamente: concentração de Pb na água, em ng.mL-1, não detectado (nd) - 55,56 e 19,23; Pb em sedimentos, em µg.g-1, 48,73 - 92,87 e 71,93; pH, 7,02 - 8,23 e 7,60; temperatura, em °C, 19,33 - 27,48 e 23,73; DQO, em mg.L-1, 13,33 - 30,11 e 23,54. Uma análise dos resultados das variáveis medidas, em nível de 5% de significância permitem concluir que a concentração de Pb na água é independente dos pontos de coleta (local), mas, dependente do período de amostragem (temporalidade) e nos sedimentos dependente dos dois parâmetros.<br>This work introduce the study of lead dynamic in the lake of Ingá Park, Maringá - PR. Monthly, during a year, samples of water and sediments were collected and pH and temperature measured. In the water samples were determined the chemical oxygen demand (COD) and the total lead concentration in water and sediment samples. The determination of lead concentration in water and sediments was performed with atomic absorption spectrometer - flame technique. The monthly mean values found, presented in intervals and global mean values, were respectively: lead concentration in water (ng.mL-1), non detected (nd) - 55.56 and 19.23; lead in sediments (µg.g-1), 48.73 - 92.87 and 71.93; pH, 7.02 - 8.23 and 7.60; temperature (ºC), 19.33 - 27.48 and 23.73; COD (mg.L-1), 13.33 - 30.11 and 23.54. A survey of the lead concentration results found permit to conclude, at 5% of significance, that the lead concentration in water was independent of the sampling point (local), but dependent of the sampling period (temporality) and in the sediment dependent of the two parameters

Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated