CGRP antibody therapy in patients with drug resistant migraine and chronic daily headache: a real-world experience

Background Calcitonin gene-related peptide (CGRP) (receptor) antibodies (erenumab, fremanezumab and galcanezumab) are increasingly used in prophylactic treatment of migraine. In the approval studies, severely affected patients with migraine and chronic daily headache without any headache free days were excluded. Thus, less is known about the effectiveness of CGRP antibody treatment in this cohort. Methods Clinical routine data of 32 patients with migraine and daily headache were analysed after three months of treatment with a CGRP antibody (16 erenumab, 7 galcanezumab, 9 fremanezumab), including changes of monthly headache days (MHD) monthly migraine days (MMD) and monthly acute medication intake (AMD) as well as migraine characteristics. Statistical analysis was performed with the Wilcoxon-Test. Migraine characteristics were analysed descriptively. Results The number of MHD was significantly reduced (mean reduction (standard error), p-value): (-4.2 (1.3), p = 0.009) as well as MMD (-4.3 (1.6), p = 0.033). Four patients (13 %) reached a 50 % reduction regarding MHD and 8 patients (25 %) regarding MMD, migraine duration and intensity improved under therapy. Conclusions Despite the low responder rate, CGRP antibodies can be effective at least in a few cases of severely affected patients with drug resistant migraine and chronic daily headache. Trial registration Retrospective registered.

Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general population of the United Kingdom

We report that in a cohort of 45,965 adults, who were receiving either the ChAdOx1 or the BNT162b2 SARS-CoV-2 vaccines, in those who had no prior infection with SARS-CoV-2, seroconversion rates and quantitative antibody levels after a single dose were lower in older individuals, especially in those aged >60 years. Two vaccine doses achieved high responses across all ages. Antibody levels increased more slowly and to lower levels with a single dose of ChAdOx1 compared with a single dose of BNT162b2, but waned following a single dose of BNT162b2 in older individuals. In descriptive latent class models, we identified four responder subgroups, including a ‘low responder’ group that more commonly consisted of people aged >75 years, males and individuals with long-term health conditions. Given our findings, we propose that available vaccines should be prioritized for those not previously infected and that second doses should be prioritized for individuals aged >60 years. Further data are needed to better understand the extent to which quantitative antibody responses are associated with vaccine-mediated protection.

P–220 Delayed-ICSI on day1-matured oocytes in low responders of different age groups

Study question Is the cycle outcome of day0-ICSI (day0-matured oocytes) and delayed-ICSI (day1-matured oocytes) in low responders affected by maternal age? Summary answer Delayed-ICSI improves cycle outcome of low responders in all age groups by providing additional blastocysts for embryo transfer and/or pre-implantation genetic testing for aneuploidies (PGT-A). What is known already We had previously compared the fertilization, blastulation, blastocyst utilisation, and euploidy rates between day0-ICSI and delayed-ICSI (Lee, C.S.S., 2018). We believed that patients who have <7 mature oocytes (low responders) can benefit by having their concomitant immature oocytes cultured to day 1. This study evaluates the benefit of delayed-ICSI in improving the cycle outcome of such low responders from different age groups. Study design, size, duration From January 2018 to December 2020, 434 IVF cycles in Alpha IVF & Women’s Specialists were classified as low responder (being <7 oocytes injected on day 0). The immature oocytes were further cultured and delayed-ICSI was done on day1-matured oocytes. Patients were divided into 3 groups: (A) ≤35 years old (n = 137; mean maternal age=32.5; range=23.0–35.0); (B) 36–40 years old (n = 208; mean maternal age=38.2; range=36.0–40.0); and (C) >40 years old (n = 89; mean maternal age=42.7; range=41.0–49.0). Participants/materials, setting, methods Semen samples were processed by density gradient centrifugation and/or swim-up method. Day0-matured oocytes were injected at 2.5–4.5 hours post-retrieval (PIEZO, Japan). Immature oocytes were further cultured for 18–24hours and delayed-ICSI was done immediately after maturity assessment. Injected oocytes were cultured up to 7 days and trophectoderm biopsy for PGT-A screening (IonTorrent, USA) was performed on selected blastocysts prior to vitrification (Cryotec, Japan). The cycle outcomes of day0-ICSI and delayed-ICSI were analysed and compared. Main results and the role of chance In Group A, the fertilisation, blastulation, blastocyst utilisation and euploidy rates of day0-ICSI and day1-ICSI were 80.0% vs. 70.9%, 74.7% vs. 33.6%, 57.1% vs. 17.9%, and 52.3% vs. 30.8% respectively. The fertilisation (p = 0.0024), blastulation (p = 0.0001), utilization (p = 0.001) and euploidy (p = 0.0205) rates of delayed-ICSI were significantly lower compared to day0-ICSI. In Group B, the fertilisation, blastulation, blastocyst utilisation and euploidy rates of day0-ICSI and day1-ICSI were 77.3% vs. 64.1%, 75.0% vs. 37.5%, 52.7% vs. 20.6% and 26.0% vs. 32.1% respectively. Delayed-ICSI showed significantly lower fertilisation (p = 0.0001), blastulation (p = 0.0001) and utilization (p = 0.0001) rates than day0-ICSI, but the euploidy rate was comparable (p = 03997). In Group C, the fertilisation, blastulation and blastocyst utilisation rates of day0-ICSI and delayed-ICSI were 76.6% vs. 56.4%, 67.1% vs. 22.8%, 34.3% vs. 7.9% respectively. Similar to Group B, the fertilization (p = 0.0001), blastulation (p = 0.0001) and utilisation (p = 0.0003) rates in day0-ICSI was significantly higher than delayed-ICSI. No significant difference was observed between the euploidy rates of day0-ICSI and delayed-ICSI (18.9% vs. 0.0%, p = 0.3452). Despite all blastocysts derived from delayed-ICSI in this group being aneuploid, it could still increase the chances of these patients obtaining an euploid blastocyst. Limitations, reasons for caution Analysis on Group B was done on a larger sample size compared to Group A and C. A larger sample size in Group A and C is needed to further support our results. Wider implications of the findings: Delayed-ICSI generates additional blastocysts for low responders from all age groups. Therefore, delayed-ICSI could be a routine procedure in low responder IVF patients in order to optimise the cycle and clinical outcomes. Trial registration number Not applicable

Myokine Responses to Exercise in a Rat Model of Low/High Adaptive Potential

IntroductionAssuming myokines underlie some of the health benefits of exercise, we hypothesised that ‘high responder trainer’ (HRT) rats would exhibit distinct myokine profiles to ‘low responder trainers’ (LRT), reflecting distinct health and adaptive traits.MethodsBlood was collected from LRT and HRT (N=8) rats at baseline (BL), immediately (0h), 1h, and 3h after running; repeated after 3-wks training. Myokines were analysed by ELISA (i.e. BDNF/Fractalkine/SPARC/Irisin/FGF21/Musclin/IL-6).ResultsAt baseline, Musclin (LRT: 84 ± 24 vs HRT: 26 ± 3 pg/ml, P=0.05) and FGF21 (LRT: 133 ± 34 vs HRT: 63.5 ± 13 pg/ml, P=0.08) were higher in LRT than HRT. Training increased Musclin in HRT (26 ± 3 to 54 ± 9 pg/ml, P<0.05) and decreased FGF21 in LRT (133 ± 34 to 60 ± 28 pg/ml, P<0.05). Training increased SPARC (LRT: 0.8 ± 0.1 to 2.1 ± 0.6 ng/ml, P<0.05; HRT: 0.7 ± 0.06 to 1.8 ± 0.3 ng/ml, P=0.06) and Irisin (LRT 0.62 ± 0.1 to 2.6 ± 0.4 ng/ml, P<0.01; HRT 0.53 ± 0.1 to 2.8 ± 0.7 ng/ml, P<0.01) while decreasing BDNF (LRT: 2747 ± 293 to 1081 ± 330 pg/ml, P<0.01; HRT: 1976 ± 328 to 797 ± 160 pg/ml, P<0.05). Acute exercise response of Musclin (AUC) was higher in LRT vs HRT (306 ± 74 vs. 88 ± 12 pg/ml×3h-1, P<0.01) and elevated in HRT after training (221 ± 31 pg/ml×3h-1, P<0.01). Training elevated SPARC (LRT: 2.4 ± 0.1 to 7.7 ± 1.3 ng/ml×3h-1, P<0.05; HRT: 2.5 ± 0.13 to 11.2 ± 2.2 ng/ml×3h-1, P<0.001) and Irisin (LRT: 1.34 ± 0.3 to 9.6 ± 1.7 ng/ml×3h-1, P<0.001; HRT: 1.5 ± 0.5 to 12.1 ± 1.9 ng/ml×3h-1, P<0.0001).ConclusionExercise training alters how myokines are secreted in response to acute exercise. Myokine responses were not robustly linked to adaptive potential in aerobic capacity, making them an unlikely regulator of adaptive traits.

CYP7A1, NPC1L1, ABCB1, and CD36 Polymorphisms Are Associated with Increased Serum Coenzyme Q10 after Long-Term Supplementation in Women

Coenzyme Q10 (CoQ10), an essential component for energy production that exhibits antioxidant activity, is considered a health-supporting and antiaging supplement. However, intervention-controlled studies have provided variable results on CoQ10 supplementation benefits, which may be attributed to individual CoQ10 bioavailability differences. This study aimed to investigate the relationship between genetic polymorphisms and CoQ10 serum levels after long-term supplementation. CoQ10 levels at baseline and after one year of supplementation (150 mg) were determined, and eight single nucleotide polymorphisms (SNPs) in cholesterol metabolism and CoQ10 absorption, efflux, and cellular uptake related genes were assessed. Rs2032582 (ABCB1) and rs1761667 (CD36) were significantly associated with a higher increase in CoQ10 levels in women. In addition, in women, rs3808607 (CYP7A1) and rs2072183 (NPC1L1) were significantly associated with a higher increase in CoQ10 per total cholesterol levels. Subgroup analyses showed that these four SNPs were useful for classifying high- or low-responder to CoQ10 bioavailability after long-term supplementation among women, but not in men. On the other hand, in men, no SNP was found to be significantly associated with increased serum CoQ10. These results collectively provide novel evidence on the relationship between genetics and CoQ10 bioavailability after long-term supplementation, which may help understand and assess CoQ10 supplementation effects, at least in women.

Development and Use of a Seedling Growth Retardation Assay to Quantify and Map Loci Underlying Variation in the Maize Basal Defense Response

The pattern-triggered immune (PTI) response in plants is caused by the recognition of conserved microbe‐ or pathogen‐associated molecular patterns (MAMPs) by plant pattern recognition receptors at the cell surface. The goal of this study was to develop a simple, robust assay to quantify the PTI response in maize and to determine whether it could be used to predict levels of disease resistance. Flg22, an epitope derived from bacterial flagellin, is a commonly studied MAMP. We developed a seedling growth retardation (SGR) assay by which we could measure growth retardation in maize seedlings exposed to the bacterial MAMP flg22. We observed variation across 21 maize inbred lines. We used 161 lines from a recombinant inbred line (RIL) population derived from a cross between the lines CML228 (a high responder) and B73 (a low responder) to map quantitative trait loci (QTL) for this response. We found heritable variation in the RIL population and identified flg22 response QTL on chromosomes 1, 2, and 8. We did not observe strong correlations between SGR traits and levels of flg22-induced reactive oxygen production or with other disease resistance or defense response traits we had previously measured in the same population. We discuss the implications of these findings. [Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

P0509CLINICAL ANALYSIS FOR PROGNOSTIC FACTORS BASED ON RESULTS OF VERY SHORT-TERM TREATMENT IN MEMBRANOUS NRPHROPATHY

Background and Aims Membranous nephropathy (MN) is known to affect frequently in elderly patients. Since the duration of MN treatment is likely to be prolonged, it is desirable that the treatment duration would be shortened by the concomitant use of immunosuppressant and prednisolone (PSL). Therefore, we evaluated prognostic factors using the results of treatment in a very short period of time in patients with membrane nephropathy at our hospital. Method Biopsy-proven 66 cases with MN, hospitalized between April 2009 and December 2017, were enrolled in this study. All cases were divided between two groups, high responder and low responder, based on the 50% proteinuria-reduction ratio at a month after the beginning of therapy including sole administration of PSL and concomitant use of immunosuppressants such as Cyclosporin or Mizoribine. High responder and low responder were comparatively studied. All biopsy specimens were stained by anti-phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain containing 7A (THSD7A) antibodies by standard protocol. Results Estimated glomerular filtration rate (eGFR) was 70.5 vs 60.4 ml/min (p = 0.087), showing no difference. Baseline urine protein-to-Cr ratio (PCR) and degree of hematuria in high responder were significantly higher than those in low responder; baseline PCR: (6.95 vs 3.86, p = 0.003), degree of hematuria: (1 vs 0, p = 0.036) There was no difference in intensity of immunofluorescent staining of IgG, A, M, C3 between high responder and low responder. We also studied the difference in immunofluorescent intensity of PLA2R, THSD7A and IgG subclass. Intensity of IgG3 and ratio of PLA2R/IgG4 intensity in low responder were significantly higher than those in high responder; IgG3 intensity: (0 vs 0.5, p = 0.049), PLA2R/IgG4 ratio: (0.58 vs 1.00, p = 0.029) Conclusion Obtained results showed that higher baseline PCR and degree of hematuria might be related to the rapid therapeutical response. On the other hand, higher staining intensity of IgG3 and PLA2R/IgG4 intensity ratio might reduce the response of treatment.