Indirect effects of paediatric conjugate vaccines on invasive pneumococcal disease in older adults

Objectives: The aim of this study was to assess the indirect effect of paediatric 13-valent pneumococcal conjugate vaccine (PCV13) vaccination on people ≥65 years of age with invasive pneumococcal disease (IPD) in Catalonia and to determine factors predictive of mortality. Methods: During 2014-2016, 1285 IPD cases were reported to the Public Health Agency of Catalonia. The indirect effect of paediatric PCV13 vaccination was calculated by comparing the incidence rate (IR) in 2016 (PCV13 year) with that in 2009 (pre-PCV13). Predictors of mortality were determined using multivariate logistic regression. Results: Comparing 2016 and 2009, IPD decreased by 19% (IR 40.1 and 32.5 per 100 000 person-years, respectively). PCV13 serotypes decreased by 57% (IR 23.7 and 10.1), while non-PCV13 serotypes increased by 36% (IR 16.4 and 22.4). During 2014-2016, the mortality rate was 17.5%, and mortality was associated with age ≥85 years (adjusted odds ratio (aOR) 2.91, 95% confidence interval (CI) 1.89, 4.48), meningitis (aOR 2.29, 95% CI 1.25, 4.19), non-focal bacteraemia (aOR 3.73, 95% CI 2.00, 6.94), and ≥1 high-risk condition (aOR 1.89, 95% CI 1.08, 3.32). PPV23non13 serotypes were associated with lower mortality than PCV13 serotypes (aOR 0.54, 95% CI 0.34, 0.86). Conclusions: The incidence of IPD in people ≥65 years of age decreased after the introduction of paediatric PCV13, and this was due to a reduction in PCV13 serotypes, although an increase in non-PCV13 serotypes was observed. Mortality was associated with age, meningitis, non-focal bacteraemia, ≥1 high-risk condition, and PCV13 serotypes

Indirect effects of paediatric conjugate vaccines on invasive pneumococcal disease in older adults

Streptococcus pneumoniae; IPD; PCV13; Adults; Case fatality rate; Comorbidities; MortalitySteotococos neumonia; IPD; PCV13; Adultos; Tasa de letalidad; Comorbilidades; MortalidadStreptococcus pneumoniae; IPD; PCV13; Adults; Taxa de letalitat; Comorbiditats; MortalitatObjectives The aim of this study was to assess the indirect effect of paediatric 13-valent pneumococcal conjugate vaccine (PCV13) vaccination on people ≥65 years of age with invasive pneumococcal disease (IPD) in Catalonia and to determine factors predictive of mortality. Methods During 2014–2016, 1285 IPD cases were reported to the Public Health Agency of Catalonia. The indirect effect of paediatric PCV13 vaccination was calculated by comparing the incidence rate (IR) in 2016 (PCV13 year) with that in 2009 (pre-PCV13). Predictors of mortality were determined using multivariate logistic regression. Results Comparing 2016 and 2009, IPD decreased by 19% (IR 40.1 and 32.5 per 100 000 person-years, respectively). PCV13 serotypes decreased by 57% (IR 23.7 and 10.1), while non-PCV13 serotypes increased by 36% (IR 16.4 and 22.4). During 2014–2016, the mortality rate was 17.5%, and mortality was associated with age ≥85 years (adjusted odds ratio (aOR) 2.91, 95% confidence interval (CI) 1.89, 4.48), meningitis (aOR 2.29, 95% CI 1.25, 4.19), non-focal bacteraemia (aOR 3.73, 95% CI 2.00, 6.94), and ≥1 high-risk condition (aOR 1.89, 95% CI 1.08, 3.32). PPV23non13 serotypes were associated with lower mortality than PCV13 serotypes (aOR 0.54, 95% CI 0.34, 0.86). Conclusions The incidence of IPD in people ≥65 years of age decreased after the introduction of paediatric PCV13, and this was due to a reduction in PCV13 serotypes, although an increase in non-PCV13 serotypes was observed. Mortality was associated with age, meningitis, non-focal bacteraemia, ≥1 high-risk condition, and PCV13 serotypes

Pediatric Parapneumonic Empyema, Spain

Increased incidence is principally due to highly invasive nonvaccine serotypes of pneumococci, especially serotype 1

Failures of 13-Valent Conjugated Pneumococcal Vaccine in Age-Appropriately Vaccinated Children 2-59 Months of Age, Spain

Vaccination with the 13-valent conjugated pneumococcal disease (PCV13) has reduced invasive pneumococcal disease (IPD), but there have been reports of vaccine failures. We performed a prospective study in children aged 2-59 months who received diagnoses of IPD during January 2012-June 2016 in 3 pediatric hospitals in Catalonia, Spain, a region with a PCV13 vaccination coverage of 63%. We analyzed patients who had been age-appropriately vaccinated but who developed IPD caused by PCV13 serotypes. We detected 24 vaccine failure cases. The serotypes involved were 3 (16 cases); 19A (5 cases); and 1, 6B, and 14 (1 case each). Cases were associated with children without underlying conditions, with complicated pneumonia (OR 6.65, 95% CI 1.91-23.21), and with diagnosis by PCR (OR 5.18, 95% CI 1.84-14.59). Vaccination coverage should be increased to reduce the circulation of vaccine serotypes. Continuous surveillance of cases of IPD using both culture and PCR to characterize vaccine failures is necessary

Membrane-bound guaiacol peroxidases from maize (Zea mays L.) roots are regulated by methyl jasmonate, salicylic acid, and pathogen elicitors

Plant peroxidases are involved in numerous cellular processes in plant development and stress responses. Four plasma membrane-bound peroxidases have been identified and characterized in maize (Zea mays L.) roots. In the present study, maize seedlings were treated with different stresses and signal compounds, and a functional analysis of these membrane-bound class III peroxidases (pmPOX1, pmPOX2a, pmPOX2b, and pmPOX3) was carried out. Total guaiacol peroxidase activities from soluble and microsomal fractions of maize roots were compared and showed weak changes. By contrast, total plasma membrane and washed plasma membrane peroxidase activities, representing peripheral and integral membrane proteins, revealed strong changes after all of the stresses applied. A proteomic approach using 2D-PAGE analysis showed that pmPOX3 was the most abundant class III peroxidase at plasma membranes of control plants, followed by pmPOX2a >pmPOX2b >pmPOX1. The molecular mass (63 kDa) and the isoelectric point (9.5) of the pmPOX2a monomer were identified for the first time. The protein levels of all four enzymes changed in response to multiple stresses. While pmPOX2b was the only membrane peroxidase down-regulated by wounding, all four enzymes were differentially but strongly stimulated by methyl jasmonate, salicylic acid, and elicitors (Fusarium graminearum and Fusarium culmorum extracts, and chitosan) indicating their function in pathogen defence. Oxidative stress applied as H2O2 treatment up-regulated pmPOX2b >pmPOX2a, while pmPOX3 was down-regulated. Treatment with the phosphatase inhibitor chantharidin resulted in distinct responses

Trends in invasive bacterial diseases during the first 2 years of the COVID-19 pandemic: analyses of prospective surveillance data from 30 countries and territories in the IRIS Consortium.

BACKGROUND The Invasive Respiratory Infection Surveillance (IRIS) Consortium was established to assess the impact of the COVID-19 pandemic on invasive diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae. We aimed to analyse the incidence and distribution of these diseases during the first 2 years of the COVID-19 pandemic compared to the 2 years preceding the pandemic. METHODS For this prospective analysis, laboratories in 30 countries and territories representing five continents submitted surveillance data from Jan 1, 2018, to Jan 2, 2022, to private projects within databases in PubMLST. The impact of COVID-19 containment measures on the overall number of cases was analysed, and changes in disease distributions by patient age and serotype or group were examined. Interrupted time-series analyses were done to quantify the impact of pandemic response measures and their relaxation on disease rates, and autoregressive integrated moving average models were used to estimate effect sizes and forecast counterfactual trends by hemisphere. FINDINGS Overall, 116 841 cases were analysed: 76 481 in 2018-19, before the pandemic, and 40 360 in 2020-21, during the pandemic. During the pandemic there was a significant reduction in the risk of disease caused by S pneumoniae (risk ratio 0·47; 95% CI 0·40-0·55), H influenzae (0·51; 0·40-0·66) and N meningitidis (0·26; 0·21-0·31), while no significant changes were observed for S agalactiae (1·02; 0·75-1·40), which is not transmitted via the respiratory route. No major changes in the distribution of cases were observed when stratified by patient age or serotype or group. An estimated 36 289 (95% prediction interval 17 145-55 434) cases of invasive bacterial disease were averted during the first 2 years of the pandemic among IRIS-participating countries and territories. INTERPRETATION COVID-19 containment measures were associated with a sustained decrease in the incidence of invasive disease caused by S pneumoniae, H influenzae, and N meningitidis during the first 2 years of the pandemic, but cases began to increase in some countries towards the end of 2021 as pandemic restrictions were lifted. These IRIS data provide a better understanding of microbial transmission, will inform vaccine development and implementation, and can contribute to health-care service planning and provision of policies. FUNDING Wellcome Trust, NIHR Oxford Biomedical Research Centre, Spanish Ministry of Science and Innovation, Korea Disease Control and Prevention Agency, Torsten Söderberg Foundation, Stockholm County Council, Swedish Research Council, German Federal Ministry of Health, Robert Koch Institute, Pfizer, Merck, and the Greek National Public Health Organization

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification