•The persistence of humoral responses are different between vaccines.•After ChAd/ChAd, mRNA vaccines still have the highest humoral response at day 84.•After BNT/BNT viral-vector vaccines have ...comparable or even higher humoral response at D84 compared with homologous BNT boost schedule.•Heterologous and homologous schedules have different kinetics of antibody titre decline by day 84 which appears to depend both on vaccine class and order of administration.•Half dose BNT induced comparable levels of humoral and cellular responses at day 84 compared with full dose BNT.
To evaluate the persistence of immunogenicity three months after third dose boosters.
COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose. The analysis was conducted using all randomised participants who were SARS-CoV-2 naïve during the study.
Amongst the 2883 participants randomised, there were 2422 SARS-CoV-2 naïve participants until D84 visit included in the analysis with median age of 70 (IQR: 30–94) years. In the participants who had two initial doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd), schedules using mRNA vaccines as third dose have the highest anti-spike IgG at D84 (e.g. geometric mean concentration of 8674 ELU/ml (95% CI: 7461–10,085) following ChAd/ChAd/BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT)). However, in people who had two initial doses of BNT there was no significant difference at D84 in people given ChAd versus BNT (geometric mean ratio (GMR) of 0.95 (95%CI: 0.78, 1.15). Also, people given Ad26.COV2.S (Janssen; hereafter referred to as Ad26) as a third dose had significantly higher anti-spike IgG at D84 than BNT (GMR of 1.20, 95%CI: 1.01,1.43). Responses at D84 between people who received BNT (15 μg) or BNT (30 μg) after ChAd/ChAd or BNT/BNT were similar, with anti-spike IgG GMRs of half-BNT (15 μg) versus BNT (30 μg) ranging between 0.74–0.86. The decay rate of cellular responses were similar between all the vaccine schedules and doses.
84 days after a third dose of COVID-19 vaccine the decay rates of humoral response were different between vaccines. Adenoviral vector vaccine anti-spike IgG concentrations at D84 following BNT/BNT initial doses were similar to or even higher than for a three dose (BNT/BNT/BNT) schedule. Half dose BNT immune responses were similar to full dose responses. While high antibody tires are desirable in situations of high transmission of new variants of concern, the maintenance of immune responses that confer long-lasting protection against severe disease or death is also of critical importance. Policymakers may also consider adenoviral vector, fractional dose of mRNA, or other non-mRNA vaccines as third doses.
COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent messenger RNA (mRNA) COVID-19 vaccines were ...subsequently widely used for the third and fourth-dose vaccination campaigns in high-income countries. Real-world vaccine effectiveness against symptomatic infections following third doses declined during the Omicron wave. This report compares the immunogenicity and kinetics of responses to third doses of vaccines from day (D) 28 to D242 following third doses in seven study arms.
The trial initially included ten experimental vaccine arms (seven full-dose, three half-dose) delivered at three groups of six sites. Participants in each site group were randomised to three or four experimental vaccines, or MenACWY control. The trial was stratified such that half of participants had previously received two primary doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) and half had received two doses of BNT162b2 (Pfizer–BioNtech, hereafter referred to as BNT). The D242 follow-up was done in seven arms (five full-dose, two half-dose). The BNT vaccine was used as the reference as it was the most commonly deployed third-dose vaccine in clinical practice in high-income countries. The primary analysis was conducted using all randomised and baseline seronegative participants who were SARS-CoV-2 naïve during the study and who had not received a further COVID-19 vaccine for any reason since third dose randomisation.
Among the 817 participants included in this report, the median age was 72 years (IQR: 55–78) with 50.7% being female. The decay rates of anti-spike IgG between vaccines are different among both populations who received initial doses of ChAd/ChAd and BNT/BNT. In the population that previously received ChAd/ChAd, mRNA vaccines had the highest titre at D242 following their vaccine dose although Ad26. COV2. S (Janssen; hereafter referred to as Ad26) showed slower decay. For people who received BNT/BNT as their initial doses, a slower decay was also seen in the Ad26 and ChAd arms. The anti-spike IgG became significantly higher in the Ad26 arm compared to the BNT arm as early as 3 months following vaccination. Similar decay rates were seen between BNT and half-BNT; the geometric mean ratios ranged from 0.76 to 0.94 at different time points. The difference in decay rates between vaccines was similar for wild-type live virus-neutralising antibodies and that seen for anti-spike IgG. For cellular responses, the persistence was similar between study arms.
Heterologous third doses with viral vector vaccines following two doses of mRNA achieve more durable humoral responses compared with three doses of mRNA vaccines. Lower doses of mRNA vaccines could be considered for future booster campaigns.
•Humoral responses following booster doses of adenoviral vector vaccines decay slower than following booster doses of mRNA vaccines.•Lower doses of mRNA vaccines as boosters may be equally as effective.•Further investigation into heterologous vaccine schedules for COVID-19 is warranted.
Anti-tumour necrosis factor anti-TNF therapy is widely used for the treatment of inflammatory bowel disease, yet many patients are primary non-responders, failing to respond to induction therapy. We ...aimed to identify blood gene expression differences between primary responders and primary non-responders to anti-TNF monoclonal antibodies infliximab and adalimumab, and to predict response status from blood gene expression and clinical data.
The Personalised Anti-TNF Therapy in Crohn's Disease PANTS study is a UK-wide prospective observational cohort study of anti-TNF therapy outcome in anti-TNF-naive Crohn's disease patients ClinicalTrials.gov identifier: NCT03088449. Blood gene expression in 324 unique patients was measured by RNA-sequencing at baseline week 0, and at weeks 14, 30, and 54 after treatment initiation total sample size = 814.
After adjusting for clinical covariates and estimated blood cell composition, baseline expression of major histocompatibility complex, antigen presentation, myeloid cell enriched receptor, and other innate immune gene modules was significantly higher in anti-TNF responders vs non-responders. Expression changes from baseline to week 14 were generally of consistent direction but greater magnitude i.e. amplified in responders, but interferon-related genes were upregulated uniquely in non-responders. Expression differences between responders and non-responders observed at week 14 were maintained at weeks 30 and 54. Prediction of response status from baseline clinical data, cell composition, and module expression was poor.
Baseline gene module expression was associated with primary response to anti-TNF therapy in PANTS patients. However, these baseline expression differences did not predict response with sufficient sensitivity for clinical use.
We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment and to define the factors that predict anti-TNF treatment failure and the strategies that ...prevent or mitigate loss of response.
Personalised Anti-TNF therapy in Crohn's disease (PANTS) is a UK-wide, multicentre, prospective observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients with active luminal Crohn's disease aged 6 years and older. At the end of the first year, sites were invited to enrol participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449, and is now complete.
Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and 209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age 32·5 years IQR 22·1–46·8, 307 51% of 598 were female, and 291 49% were male). The estimated proportion of patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7–43·7), 34·4% (29·9–39·0), and 34·7% (29·8–39·5), and for adalimumab 35·9% (95% CI 31·2–40·5), 32·9% (26·8–39·2), and 28·9% (21·9–36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later timepoints were 6·1–10·0 mg/L for infliximab and 10·1–12·0 mg/L for adalimumab. After excluding patients who had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3 were, for infliximab 34·4% (95% CI 30·4–38·2), 54·5% (49·4–59·0), and 60·0% (54·1–65·2), and for adalimumab 32·1% (26·7–37·1), 47·2% (40·2–53·4), and 68·4% (50·9–79·7), respectively. In multivariable analysis, loss of response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug concentrations at week 14 (infliximab: hazard ratio HR for each ten-fold increase in drug concentration 0·45 95% CI 0·30–0·67, adalimumab: 0·39 0·22–0·70). For patients treated with infliximab, loss of response was also associated with female sex (vs male sex; HR 1·47 95% CI 1·11–1·95), obesity (vs not obese 1·62 1·08–2·42), baseline white cell count (1·06 1·02–1·11) per 1 × 109 increase in cells per L), and thiopurine dose quartile. Among patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response (HR 1·95 95% CI 1·17–3·25). By the end of year 3, the estimated proportion of patients who developed anti-drug antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1–49·4) among patients treated with infliximab and 20·3% (13·8–26·2) among those treated with adalimumab. The development of anti-drug antibodies associated with undetectable drug concentrations was significantly associated with treatment without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40 95% CI 0·31–0·52, adalimumab 0·42 95% CI 0·24–0·75), and with carriage of HLA-DQA1*05 risk variant for infliximab (HR for carriage of risk variant: infliximab 1·46 1·13–1·88) but not for adalimumab (HR 1·60 0·92–2·77). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated with increased time without the development of anti-drug antibodies associated with undetectable drug concentrations compared with use of infliximab alone (HR 2·87 95% CI 2·20–3·74) or introduction of an immunomodulator after anti-TNF initiation (1·70 1·11–2·59). In years 2 and 3, 16 (4%) of 389 patients treated with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal. Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections in years 2 and 3.
Only around a third of patients with active luminal Crohn's disease treated with an anti-TNF drug were in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment, particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05 and mitigated by concomitant immunomodulator use for both drugs.
Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion Healthcare.
The China Questions Rudolph, Jennifer; Szonyi, Michael
2018, 2018-01-15
eBook
Many books offer information about the world's most populous country, but few make sense of what is truly at stake. Thirty of the world's leading China experts—affiliates of Harvard's renowned ...Fairbank Center for Chinese Studies—answer key questions about where this new superpower is headed and what makes its people and their leaders tick.
Polymix breeding with paternity analysis (PMX/WPA) has been proposed as an alternative to traditional full-sib breeding and testing schemes. To fully capture the benefits of PMX/WPA, differential ...reproductive success (DRS) of pollen parents used in the polymix must be modest. DRS was evaluated in an operational test of PMX/WPA for a hybrid poplar breeding program. A 16-parent pollen polymix (Populus nigra L.) was used to pollinate seven clones of Populus deltoides (Bartr. ex. Marshall) under greenhouse breeding conditions. Progeny were grown out briefly and randomly sampled (357) prior to out-planting in field trials. Twenty-eight simple sequence repeat (SSR) loci were evaluated and 15 were selected for genetic characterization in small populations of three Populus spp (P. nigra, P. deltoides, and P. balsamifera spp trichocarpa Torr. & Gray). Seven loci were ultimately selected for paternity analysis of progeny. The average exclusion probability of the seven loci in P. nigra was 0.604; combined, the theoretical exclusion probability was 0.9999. However, only 95% of sampled progeny were unambiguously assigned a single paternal parent. Missing data likely accounted for most of the ambiguity. DRS was statistically significant though not prohibitive for practical utility of PMX/WPA as a breeding system. Of the 112 potential crosses in this study, 92 were represented. Eight of the 16 pollen parents contributed 83% of the progeny. Good pollen vigor, as measured by germination percent, did not ensure paternal success, but poor vigor was associated with lack of paternal success. PMX/WPA appears to be logistically and economically attractive for hybrid poplar breeding and testing.
Nursing care of the paratrend 7 sensor Saich, Claire; Graystone, Stephen J.; Hendry, Stuart P. ...
Intensive & critical care nursing
13, Issue:
6
Journal Article
Peer reviewed
The Paratrend 7 sensor is a continuous intravascular blood gas sensor that consists of a miniaturized Clark-type PO
2 electrode, fibreoptic pH and PCO
2 optodes and a thermocouple. the monitor ...continuously displays the measured pH, PaO
2 PaCO
2 and temperature of the blood, and the calculated oxygen saturation, BE and SBC. After 7 years of caring for over 200 patients following insertion of the sensor, we describe our nursing experience with particular emphasis on the adequate fixation of the cannula, sensor system and connectors. The maintenance of the sensor through adequate flushing of the arterial line and care of the insertion site is described. Also outlined are the potential advantages to nursing practice of this new monitoring system, with particular reference to early warning of deterioration in respiratory function, closer control of mechanical ventilation and reduction in blood gas sampling and the errors inherent therein.
