Core Outcome Set for IgE ‐mediated food allergy clinical trials and observational studies of interventions: International Delphi consensus study ‘ COMFA ’

Background: IgE‐mediated food allergy (FA) is a global health concern with substantial individual and societal implications. While diverse intervention strategies have been researched, inconsistencies in reported outcomes limit evaluations of FA treatments. To streamline evaluations and promote consistent reporting, the Core Outcome Measures for Food Allergy (COMFA) initiative aimed to establish a Core Outcome Set (COS) for FA clinical trials and observational studies of interventions. Methods: The project involved a review of published clinical trials, trial protocols and qualitative literature. Outcomes found as a result of review were categorized and classified, informing a two‐round online‐modified Delphi process followed by hybrid consensus meeting to finalize the COS. Results: The literature review, taxonomy mapping and iterative discussions with diverse COMFA group yielded an initial list of 39 outcomes. The iterative online and in‐person meetings reduced the list to 13 outcomes for voting in the formal Delphi process. One more outcome was added based on participant suggestions after the first Delphi round. A total of 778 participants from 52 countries participated, with 442 participating in both Delphi rounds. No outcome met a priori criteria for inclusion, and one was excluded as a result of the Delphi. Thirteen outcomes were brought to the hybrid consensus meeting as a result of Delphi and two outcomes, ‘allergic symptoms’ and ‘quality of life’ achieved consensus for inclusion as ‘core’ outcomes. Conclusion: In addition to the mandatory reporting of adverse events for FA clinical trials or observational studies of interventions, allergic symptoms and quality of life should be measured as core outcomes. Future work by COMFA will define how best to measure these core outcomes

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Cellular Transport and Bioactivity of a Major Saffron Apocarotenoid, Picrocrocin (4-(β‑d‑Glucopyranosyloxy)-2,6,6-trimethyl-1-cyclohexene-1-carboxaldehyde)

The cellular transport and bioactivity of the second major saffron apocarotenoid, picrocrocin, was examined in parallel to that of the major group, crocetin sugar esters, in aqueous extracts. The transport of pure picrocrocin was investigated in comparison to that of other saffron apocarotenoids, <i>trans</i>-crocetin (di-β-d-gentiobiosyl) ester and crocetin using the Caco-2 cell model coupled with an in vitro digestion procedure. RP-HPLC-DAD was employed to quantify the bioaccessible and bioavailable amounts of individual apocarotenoids. Picrocrocin and crocetin sugar esters though highly bioaccessible (75% and 60%, respectively) were transported at minute quantities (0.2% and 0.5%, respectively; 10-fold lower than crocetin). Picrocrocin did not protect against oxidant-induced DNA damage in U937, human monocytic blood cells at the concentration investigated, however, it reduced the proliferation of human adenocarcinoma and hepatocarcinoma cells. Our findings may be useful for the requirements of food legislation regarding saffron preparations, in which both apocarotenoid groups coexist

Changes in Total and Individual Crocetin Esters upon in Vitro Gastrointestinal Digestion of Saffron Aqueous Extracts

Changes that may be expected in crocetin esters (crocins) upon digestion were examined in saffron aqueous extracts for the first time. Chemical characterization of total and individual crocins and other bioactive compounds was achieved by UV–vis spectrophotometry, RP-HPLC-DAD, and LC-ESI-MS. Antioxidant activity was evaluated using in vitro assays and the comet assay. The observed loss for both total and <i>trans</i>-crocins was higher in saffron (∼50%) than in gardenia extracts (∼30%), which were also examined for comparison. Loss was lower than that reported for hydrophobic carotenoids. <i>cis</i>-Isomers were less affected, leading to the hypothesis that <i>trans</i>/<i>cis</i> isomerization may occur in parallel to degradation reactions. Monitoring changes in the extracts at oral, gastric, or intestinal phases, separately, verified this view pointing out the critical effect of pH, temperature, and duration of process but not of digestive enzymes. No isomerization and less degradation (<20% loss) was evidenced when pure <i>trans</i>-crocetin (di-β-d-gentiobiosyl) ester was subjected to gastric or intestinal conditions

Clinical Frailty Scale as a predictor of adverse outcomes following aortic valve replacement: a systematic review and meta-analysis

Objectives Assessment of frailty prior to aortic valve intervention is recommended in European and North American valvular heart disease guidelines. However, there is a lack of consensus on how it is best measured. The Clinical Frailty Scale (CFS) is a well-validated measure of frailty that is relatively quick to calculate. This meta-analysis sought to examine whether the CFS predicts mortality and morbidity following either transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR).Methods Nine electronic databases were searched systematically for data on clinical outcomes post-TAVI/SAVR, where patients had undergone preoperative frailty assessment using the CFS. The primary endpoint was 12-month mortality. TAVI and SAVR data were assessed and reported separately. For each individual study, the incidence of adverse outcomes was extracted according to a CFS score of 5–9 (ie, frail) versus 1–4 (ie, non-frail), with meta-analysis performed using a random effects model.Results Of 2612 records screened, nine were included in the review (five TAVI, three SAVR and one which included both interventions). Among 4923 TAVI patients, meta-analysis showed 12-month mortality rates of 19.1% for the frail cohort versus 9.8% for the non-frail cohort (RR 2.53 (1.63 to 3.95), p&lt;0.001, I2=83%). For the smaller cohort of SAVR patients (n=454), mortality rates were 20.3% versus 3.9% for the frail and non-frail cohorts, respectively (RR 5.08 (2.31 to 11.15), p&lt;0.001, I2=5%).Conclusions Frailty, as determined by the CFS, was associated with an increased mortality risk in the 12 months following either TAVI or SAVR. These data would support its use in the preoperative assessment of elderly patients undergoing aortic valve interventions

Rockwood Clinical Frailty Scale as a predictor of adverse outcomes among older adults undergoing aortic valve replacement: a protocol for a systematic review

ntroduction Frailty is associated with adverse outcomes relating to cardiac procedures. It has been proposed that frailty scoring should be included in the preoperative assessment of patients undergoing aortic valve replacement. We aim to examine the Rockwood Clinical Frailty Scale (CFS), as a predictor of adverse outcomes following aortic valve replacement. Methods and analysis Prospective and retrospective cohort studies and randomised controlled trials assessing both the preoperative frailty status (as per the CFS) and incidence of adverse outcomes among older adults undergoing either surgical aortic valve replacement or transcatheter aortic valve replacement will be included. Adverse outcomes will include mortality and periprocedural complications, as well as a composite of 30-day complications. A search will be conducted from 2005 to present using a prespecified search strategy. Studies will be screened for inclusion by two reviewers, with methodological quality assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Relative risk ratios with 95% CIs will be generated for each outcome of interest, comparing frail with non-frail groups. Data will be plotted on forest plots where applicable. The quality of the evidence will be determined using the Grading of Recommendations, Assessment, Development and Evaluation tool

Clinical frailty scale as a predictor of adverse outcomes following aortic valve replacement: a systematic review and meta-analysis

Objectives Assessment of frailty prior to aortic valve intervention is recommended in European and North American valvular heart disease guidelines. However, there is a lack of consensus on how it is best measured. The Clinical Frailty Scale (CFS) is a well-validated measure of frailty that is relatively quick to calculate. This meta-analysis sought to examine whether the CFS predicts mortality and morbidity following either transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR). Methods Nine electronic databases were searched systematically for data on clinical outcomes post-TAVI/ SAVR, where patients had undergone preoperative frailty assessment using the CFS. The primary endpoint was 12-month mortality. TAVI and SAVR data were assessed and reported separately. For each individual study, the incidence of adverse outcomes was extracted according to a CFS score of 5–9 (ie, frail) versus 1–4 (ie, non-frail), with meta-analysis performed using a random effects model. Results Of 2612 records screened, nine were included in the review (five TAVI, three SAVR and one which included both interventions). Among 4923 TAVI patients, meta-analysis showed 12-month mortality rates of 19.1% for the frail cohort versus 9.8% for the non-frail cohort (RR 2.53 (1.63 to 3.95), p<0.001, I2 =83%). For the smaller cohort of SAVR patients (n=454), mortality rates were 20.3% versus 3.9% for the frail and non-frail cohorts, respectively (RR 5.08 (2.31 to 11.15), p<0.001, I2 =5%). Conclusions Frailty, as determined by the CFS, was associated with an increased mortality risk in the 12 months following either TAVI or SAVR. These data would support its use in the preoperative assessment of elderly patients undergoing aortic valve interventions.</p

Event rates and incidence of Post-COVID-19 condition in hospitalised SARS-CoV-2 positive children and young people and controls across different pandemic waves: exposure-stratified prospective cohort study in Moscow (StopCOVID)

BackgroundLong-term health outcomes in children and young people (CYP) after COVID-19 infection are not well understood and studies with control groups exposed to other infections are lacking. This study aimed to investigate the incidence of post-COVID-19 condition (PCC) and incomplete recovery in CYP after hospital discharge and compare outcomes between different SARS-CoV-2 variants and non-SARS-CoV-2 infections.MethodsA prospective exposure-stratified cohort study of individuals under 18 years old in Moscow, Russia. Exposed cohorts were paediatric patients admitted with laboratory-confirmed COVID-19 infection between April 2 and December 11, 2020 (Wuhan variant cohort) and between January 12 and February 19, 2022 (Omicron variant cohort). CYP admitted with respiratory and intestinal infections, but negative lateral flow rapid diagnostic test and PCR-test results for SARS-CoV-2, between January 12 and February 19, 2022, served as unexposed reference cohort. Comparison between the 'exposed cohorts' and 'reference cohort' was conducted using 1:1 matching by age and sex. Follow-up data were collected via telephone interviews with parents, utilising the long COVID paediatric protocol and survey developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The WHO case definition was used to categorise PCC.ResultsOf 2595 CYP with confirmed COVID-19, 1707 (65.7%) participated in follow-up interviews, with 1183/1707 (69%) included in the final 'matched' analysis. The median follow-up time post-discharge was 6.7 months. The incidence of PCC was significantly higher in the Wuhan variant cohort (89.7 cases per 1000 person-months, 95% CI 64.3-120.3) compared to post-infection sequalae in the reference cohort (12.2 cases per 1000 person-months, 95% CI 4.9-21.9), whereas the difference with the Omicron variant cohort and reference cohort was not significant. The Wuhan cohort had higher incidence rates of dermatological, fatigue, gastrointestinal, sensory, and sleep manifestations, as well as behavioural and emotional problems than the reference cohort. The only significant difference between Omicron variant cohort and reference cohort was decreased school attendance. When comparing the Wuhan and Omicron variant cohorts, higher incidence of PCC and event rates of fatigue, decreased physical activity, and deterioration of relationships was observed. The rate of incomplete recovery was also significantly higher in the Wuhan variant cohort than in both the reference and the Omicron variant cohorts.ConclusionsWuhan variant exhibited a propensity for inducing a broad spectrum of physical symptoms and emotional behavioural changes, suggesting a pronounced impact on long-term health outcomes. Conversely, the Omicron variant resulted in fewer post-infection effects no different from common seasonal viral illnesses. This may mean that the Omicron variant and subsequent variants might not lead to the same level of long-term health consequences as earlier variants