Humoral immunity to SARS-CoV-2 in kidney transplant recipients and dialysis patients: IgA and IgG patterns unraveled after SARS-CoV-2 infection and vaccination.

BACKGROUND: Infection with SARS-CoV-2 in high-risk groups such as kidney transplant and dialysis patients is shown to be associated with a more serious course of the disease. Four years after the start of the COVID-19 pandemic, crucial knowledge on the immune responses in these patient groups is still lacking. Therefore, this study aimed at investigating the humoral immune response after a SARS-CoV-2 infection compared to vaccination as well as the evolution of immunoglobulins over time. METHODS: Kidney transplant recipients, patients on haemodialysis or on peritoneal dialysis and healthy controls were included in this longitudinal multicenter study. SARS-CoV-2 anti-RBD, anti-NP and anti-S1S2 immunoglobulin G (IgG) and A (IgA) as well as the neutralizing antibody capacity were measured. RESULTS: Kidney transplant recipients had a significantly better humoral response to SARS-CoV-2 after infection (86.4%) than after a two-dose mRNA vaccination (55.8%) while seroconversion was comparable in patients on haemodialysis after infection (95.8%) versus vaccination (89.4%). In individuals without prior COVID-19, the IgG levels after vaccination were significantly lower in kidney transplant recipients when compared to all other groups. However, the IgA titres remained the highest in this patient group at each time point, both after infection and vaccination. A history COVID-19 was associated with higher antibody levels after double-dose vaccination in all patient categories and, while decreasing, titres remained high six months after double-dose vaccination. CONCLUSION: Kidney transplant recipients had a more robust humoral response to SARS-CoV-2 following infection compared to a two-dose mRNA vaccination, while patients on haemodialysis exhibited comparable seroconversion rates. Notably, individuals with prior COVID-19 exhibited higher IgG levels in response to vaccination. Hybrid immunity is thus the best possible defence against severe COVID-19 disease and seems also to hold up for these populations. Next, it is not clear whether the higher IgA levels in the kidney transplant recipients is beneficial for neutralizing SARS-CoV-2 or if it is a sign of disease severity.

Impact of first chemotherapy exposure on follicle activation and survival in human cryopreserved ovarian tissue.

STUDY QUESTION: Does chemotherapy exposure prior to ovarian tissue cryopreservation (OTC) impact the signaling pathways governing follicle activation and survival for prepubertal and postpubertal patients? SUMMARY ANSWER: Chemotherapy exposure prior OTC increases follicle apoptosis rates but not follicular activation, although the PI3K/AKT/mTOR and Hippo signaling pathways were modified in the cortex. WHAT IS KNOWN ALREADY: OTC is currently the only available fertility preservation procedure for children and for patients who have already started their treatment. While previous studies have not observed harmful impacts of first chemotherapy exposure on OTC outcomes, the consequences of treatment on follicle activation and survival need to be further investigated. To address this question, we evaluated signaling pathway modifications induced by chemotherapy exposure according to pubertal status. STUDY DESIGN, SIZE, DURATION: Cryopreserved ovarian tissues from postpubertal (12-29 years old, n = 8) and prepubertal (3-10 years old, n = 8) cancer patients donated for research were thawed and cultured for 24 h. Analyses of the survival of the follicles and stroma, and of the PI3K/AKT/mTOR and Hippo signaling pathways, were conducted at thawing and after culture. Ovarian fragments exposed to chemotherapy before collection were compared to non-exposed controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Histological investigations were performed to assess the distribution of the follicles, stroma fibrosis, vessel integrity, and apoptosis levels. It included follicular counting, collagen staining, immunostaining on CD31 and gH2AX, as well as TUNEL staining. To explore follicle activation in the different groups, the PI3K/AKT/mTOR and Hippo signaling pathways were investigated by gene expression analyses of isolated follicles and protein analyses on whole fragments through western blots and immunostaining. MAIN RESULTS AND THE ROLE OF CHANCE: We first assessed the impact of a first exposure to chemotherapy on the collagen density and vessels in ovarian tissues at thawing and after culture. While no differences in collagen density were observed according to age or previous treatment, the vascularization area (CD31+) was significantly lower in tissue from previously exposed patients compared to non-treated ones. Apoptosis analyses (TUNEL) revealed an acute deleterious impact on follicle survival after chemotherapy exposure without affecting the follicular density. Surprisingly, leukemic patients had a significantly higher percentage of gH2AX-positive follicles, indicating a DNA damage response, compared to the other patients. The proportion of activated follicles appeared to decrease following exposure to chemotherapy, suggesting that it at least did not increase activation process. Stable KIT LIGAND gene and protein expression and cKIT protein levels were observed among the groups, confirming the absence of activation. Analysis of the PI3K pathway did not reveal a difference in the AKT phosphorylation level between the groups, but pRPS6 was significantly higher in tissue from patients previously exposed to chemotherapy compared to that from non-exposed patients. Finally, protein and gene analyses on Hippo pathway signaling showed a higher LATS1 protein level in the cortex after chemotherapy exposure. LIMITATIONS, REASONS FOR CAUTION: The heterogeneity of the human fragments, and the limited number of patients included in the cohort have to be considered as important study limitations. Moreover, this study did not explore the long-term consequences of chemotherapy on follicular development. Therefore, the results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: These results underscore the deleterious effect of previous chemotherapeutic treatment on follicle survival. Although follicular density was not reduced, these data suggested that exposure to chemotherapy impacts follicular apoptosis and the DNA damage response. Chemotherapy-induced activation was not observed despite the impact on mTOR and Hippo signaling pathways in the whole cortex. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by an Excellence of Science (EOS) Grant (ID: 30443682) and was supported by Fonds Erasme. I.D. and M.-M.D. are associate researchers at Fonds National de la Recherche Scientifique de Belgique (FNRS). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Study of resilience and loneliness in youth (18-25 years old) during the COVID-19 pandemic lockdown measures.

This study evaluated the risks and protective factors in mental health in 825 emerging adults aged from 18 to 25 years old in Belgium and in Italy. Resilience, loneliness and social, and family context were explored to determine their specific role in coping with the emotional distress that spread worldwide during the coronavirus disease 2019 (COVID-19) pandemic. We conducted an online survey on the secured platform Research Electronic Data Capture©. Data were collected between April 7th and May 4th, 2020. The primary outcomes were the resilience scale for adults (RSA) and the University of California Los Angeles Loneliness Scale. The secondary outcomes included mental health status in terms of professional help seeking, use of psychotropic drugs, admission to a psychiatric department before and during lockdown measures. Responders were divided into three groups following the mental healthcare needs (MHCN) before and after the lockdown measures. The group who experienced an increase in MHCN represented almost 5% of the assessed youth. Statistically significant differences were found in means of RSA total score and RSA perception of self. This study enlightens the possibly traumatic impact of the COVID-19 pandemic on at-risk youth's mental health. Early detection and intervention should be structured in large-scale disasters.

Safety and efficacy of a pre-treatment antiplatelet regimen of unruptured intracranial aneurysms: a single-center experience.

PURPOSE: Endovascular treatment of unruptured intracranial aneurysms with stent-assisted coiling or flow diverter stents requires a prophylactic antiplatelet premedication to avoid thrombo-embolic complications. Guidelines for optimal antiplatelet regimens are poorly defined. The aim of this study is to report our experience using a high dosage antiplatelet premedication regimen for patients with unruptured intracranial aneurysms undergoing endovascular treatment by stent-assisted coiling or flow diverter stents. METHODS: From a retrospective analysis of a prospectively maintained database, we collected clinical and angiographic data of 400 procedures in 362 patients treated by stent-assisted coiling or flow diverter stents for 419 unruptured intracranial aneurysms. Descriptive and analytic statistics were performed to report morbidity, mortality, and complication rates and to demonstrate associations between variables and outcomes. Logistic multivariable regression was performed to rule out confounding factors between subgroups. RESULTS: Thrombo-embolic complications occurred in 23/400 procedures (5.75%) and hemorrhagic complications in 19/400 procedures (4.75%). The majority of complications were minor and transient with overall procedure-related morbidity and mortality rates of 1.75% (n = 7/400) and 1.25% (n = 5/400) respectively. The co-existence of multiple cardiovascular risk factors among smoking, hypertension, dyslipidemia, and age > 65 years old was significantly associated with permanent procedure-related morbidity (p = 0.006) and thrombo-embolic complications occurrence (p = 0.034). Age alone was associated with higher permanent morbidity (p = 0.029) and was the only variable associated with higher hemorrhagic complication (p = 0.024). CONCLUSION: In this study, the use of a high dosage antiplatelet premedication was safe and effective for the treatment of unruptured intracranial aneurysms with stent-assisted coiling or flow diverter stents. Mortality and morbidity rates compare favorably with the current literature. The thrombo-embolic complications rate is low and most of them were clinically silent. However, the hemorrhagic complications rate was substantial and a significant proportion of them were associated with mortality.

Thyrotropin (TSH) and thyroid autoimmunity are predictive factors for the incidental discovery of papillary thyroid microcarcinoma during thyroidectomy.

PURPOSE: To identify clinical, biological and pathological risk factors for the incidental discovery of papillary thyroid microcarcinomas (PTMCs) in patients undergoing thyroidectomy for presumed benign conditions. METHODS: Cross sectional, single center study, involving all consecutive patients (N = 3015) who were submitted to thyroid surgery between 2001-2019. All medical files were retrospectively reviewed. A total of 1961 patients in the benign group and 145 patients in PTMC group were analyzed. RESULTS: No significant differences in age, sex, body mass index, smoking status, thyroid volume or weight and preoperative thyroxine treatment between benign and PTMC groups were observed. Circulating anti- thyroid antibodies, histological thyroiditis and serum thyrotropin (TSH) were significantly associated with PTMC in univariable analysis. Independent risk factors for incidental PTMC by multivariable analysis where possible (OR: 1.51, 95% CI: 0.99-2.28) and certain (OR: 1.74, 95% CI: 1.09-2.78) thyroid autoimmunity (p = 0.002) and higher serum TSH (OR: 1.25, 95% CI: 1.08-1.45, p = 0.03), whereas thyroid lobectomy was associated with a lower risk of PTMC (OR: 0.40, 95% CI: 0.24-0.67, p < 0.001). The most frequent genetic alteration was BRAFV600E mutation, found in 56.3% of PTMC submitted to DNA sequencing. No association between clinical, biological or histological characteristics of PTMC and BRAFV600E mutation was observed. CONCLUSIONS: Thyroid autoimmunity and higher preoperative serum TSH level were independent predictors of PTMC incidentally discovered during thyroid surgery. Larger prospective studies are needed to better identify possible risk factors for papillary thyroid carcinoma initiation and progression.

Impact of Breast Cancer and Germline BRCA Pathogenic Variants on Fertility Preservation in Young Women.

BACKGROUND: Several studies have suggested that breast cancer (BC) and germline BRCA pathogenic variants (gBRCA PVs) could have a deleterious impact on ovarian reserve. Nevertheless, data are limited and mixed. Our objective was to evaluate the performance of fertility preservation (FP) in terms of the number of collected mature oocytes after ovarian stimulation (OS) in young women carrying a gBRCA PV, associated or not with BC. METHODS: We conducted a retrospective monocentric study at HUB-Hôpital Erasme in Brussels. All women aged between 18 and 41 years diagnosed with invasive non-metastatic BC and/or gBRCA PV carriers who underwent OS for FP or preimplantation genetic testing for monogenic disorder (PGT-M) between November 2012 and October 2021 were included. Three groups were compared: BC patients without a gBRCA PV, BC patients with a gBRCA PV, and healthy gBRCA PV carriers. Ovarian reserve was evaluated based on the efficacy of OS and AMH levels. RESULTS: A total of 85 patients underwent 100 cycles. The mean age (32.2 ± 3.9 years; p = 0.61) and median AMH level (1.9 [0.2-13] µg/L; p = 0.22) were similar between groups. Correlations between the number of mature oocytes and AMH level (p < 0.001) and between AMH and age (p < 0.001) were observed. No differences in the number of retrieved mature oocytes were observed between groups (p = 0.41), or for other OS parameters. CONCLUSION: Neither BC nor a gBRCA PV significantly affects ovarian reserve and FP efficacy in terms of the number of mature oocytes retrieved.

Sperm DNA Fragmentation after Cryopreservation and Sperm Selection Has No Implications for Clinical Pregnancies and Live Births after Intrauterine Insemination with Donor Sperm.

Intrauterine insemination with donor sperm (IUI-D) requires multiple in vitro manipulations such as sperm selection and cryopreservation during which spermatozoa may be exposed to oxidative stress (OS) and other insults that may produce potential damage including sperm DNA fragmentation (SDF). High levels of SDF, referring to damage or breaks in the genetic material of sperm cells, are linked to an increased risk of reproductive failure. This retrospective, observational study set out to evaluate whether SDF assessment could predict clinical outcome in an IUI-D program, where sperm donors are selected on strict conventional semen parameters. A total of 18 donors and 106 recipients were matched for IUI-D. Out of 429 cycles, 100 (23.3%) resulted in clinical pregnancy. We counted 78 live births (18.2% of cycles), while 20 pregnancies ended in miscarriage (4.7% of cycles), 1 in extra-uterine pregnancy and 1 in stillbirth. Female age significantly influenced clinical pregnancy and miscarriage rates. SDF increased after cryopreservation (26.3 ± 14.5%; p < 0.001) and more so after post-thaw density gradient (34.9 ± 22.1%; p = 0.04) without affecting clinical pregnancy (OR [95% CI] 1.01 [0.99; 1.02]; p = 0.27), live birth (1.00 [0.99; 1.02]; p = 0.72) and miscarriage rates (1.02 [1.00; 1.05]; p = 0.08). The implications of our findings extend to a better selection of sperm donors and a better sperm preparation technique tailored to the donor semen's properties in order to maximize the chances of a favorable treatment outcome.

Hemodynamic Tolerance of New Resistance Training Methods in Patients With Heart Failure and Coronary Artery Disease: A RANDOMIZED CROSSOVER STUDY.

PURPOSE: The purpose of this study was to determine and compare the effectiveness of three different resistance training (RT) methods for cardiac rehabilitation. METHODS: Individuals with heart failure with reduced ejection fraction (HFrEF, n = 23) or coronary artery disease (CAD, n = 22) and healthy controls (CTRL, n = 29) participated in this randomized crossover trial of RT exercises at 70% of the one-maximal repetition on a leg extension machine. Peak heart rate (HR) and blood pressure (BP) were measured noninvasively. The three RT methods were five sets of increasing repetitions from three to seven (RISE), of decreasing repetitions from seven to three (DROP), and three sets of nine repetitions (USUAL). Interset rest intervals were 15 sec for RISE and DROP and 60 sec for USUAL. RESULTS: Peak HR differed on average by <4 bpm between methods in the HFrEF and CAD groups ( P < .02). Rises in systolic BP (SBP) in the HFrEF group were comparable across methods. In the CAD group, mean SBP at peak exercise increased more in RISE and DROP than in USUAL ( P < .001), but the increase was ≤10 mm Hg. In the CTRL group, SBP was higher for DROP than for USUAL (152 ± 22 vs 144 ± 24 mm Hg, respectively; P < .01). Peak cardiac output and perceived exertion did not differ between methods. CONCLUSIONS: The RISE, DROP, and USUAL RT methods induced a similar perception of effort and similar increases in peak HR and BP. The RISE and DROP methods appear more efficient as they allow a comparable training volume in a shorter time than the USUAL method.

Clinical impact of 99mTc-MAA SPECT/CT-based personalized predictive dosimetry in selective internal radiotherapy: a real-life single-center experience in unresectable HCC patients.

BACKGROUND: Recent data demonstrated that personalized dosimetry-based selective internal radiotherapy (SIRT) is associated with better outcome for unresectable hepatocellular carcinoma (HCC). AIM: We aim to evaluate the contribution of personalized predictive dosimetry (performed with Simplicity90® software) in our population of HCC patients by comparing them to our historical cohort whose activity was determined by standard dosimetry. METHODS: This is a retrospective, single-center study conducted between February 2016 and December 2020 that included patients with HCC who received SIRT after simulation based on either standard dosimetry (group A) or, as of December 2017, on personalized dosimetry (group B). Primary endpoints were best overall response (BOR) and objective response rate (ORR) evaluated by mRECIST at 3 months. Safety and toxicity profiles were evaluated at 1- and 3-months post-treatment. For group A we compared the activity to be administered determined a posteriori using Simplicit90Y® and the activity actually administered determined by the standard approach. RESULTS: Between February 2016 and December 2020, 66 patients received 69 simulations leading to 40 treatments. The median follow-up time was equal for both groups, 21 months (range 3-55) in group A and 21 months (range 4-39) in group B. The per patient analysis revealed a significant benefit of personalized predictive dosimetry in terms of better overall response at 3 months (80% vs. 33.3%, p = 0.007) and at 6 months (77.8% vs. 22.2%, p = 0.06). This trend was found in the analysis by nodule with a response rate according to mRECIST of 87.5% for personalized dosimetry versus 68.4% for standard dosimetry at 3 months, p = 0.24. Only one grade 3 biological toxicity (hyperbilirubinemia) was noted in group A. The comparison between the administered activity and the recommended activity recalculated a posteriori using Simplicit90Y® showed that the vast majority of patients who progressed (83.33%) received less activity than that recommended by the personalized approach or an inadequate distribution of the administered activity. CONCLUSIONS: Our study aligns to recent literature and confirms that the use of personalized dosimetry allows a better selection of HCC patients who can benefit from SIRT, and consequently, improves the effectiveness of this treatment.

Association of body mass index with COVID-19 related in-hospital death.

BACKGROUND: Patients with extreme body mass indices (BMI) could have an increased risk of death while hospitalized for COVID-19. METHODS: The database of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) was used to assess the time to in-hospital death with competing-risks regression by sex and between the categories of BMI. RESULTS: Data from 12,137 patients (age 60.0 ± 16.2 years, 59% males, BMI 29.4 ± 6.9 kg/m2) of 48 countries were available. By univariate analysis, underweight patients had a higher risk of mortality than the other patients (sub-hazard ratio (SHR) 1.75 [1.44-2.14]). Mortality was lower in normal (SHR 0.69 [0.58-0.85]), overweight (SHR 0.53 [0.43-0.65]) and obese (SHR 0.55 [0.44-0.67]) than in underweight patients. Multivariable analysis (adjusted for age, chronic pulmonary disease, malignant neoplasia, type 2 diabetes) confirmed that in-hospital mortality of underweight patients was higher than overweight patients (females: SHR 0.63 [0.45-0.88] and males: 0.69 [0.51-0.94]). CONCLUSION: Even though these findings do not imply changes in the medical care of hospitalized patients, they support the use of BMI category for the stratification of patients enrolled in interventional studies where mortality is recorded as an outcome.

Order matters: sleep spindles contribute to memory consolidation only when followed by rapid-eye-movement sleep.

Sleep is known to benefit memory consolidation, but little is known about the contribution of sleep stages within the sleep cycle. The sequential hypothesis proposes that memories are first replayed during nonrapid-eye-movement (NREM or N) sleep and then integrated into existing networks during rapid-eye-movement (REM or R) sleep, two successive critical steps for memory consolidation. However, it lacks experimental evidence as N always precedes R sleep in physiological conditions. We tested this sequential hypothesis in patients with central hypersomnolence disorder, including patients with narcolepsy who present the unique, anti-physiological peculiarity of frequently falling asleep in R sleep before entering N sleep. Patients performed a visual perceptual learning task before and after daytime naps stopped after one sleep cycle, starting in N or R sleep and followed by the other stage (i.e. N-R vs. R-N sleep sequence). We compared over-nap changes in performance, reflecting memory consolidation, depending on the sleep sequence during the nap. Thirty-six patients who slept for a total of 67 naps were included in the analysis. Results show that sleep spindles are associated with memory consolidation only when N is followed by R sleep, that is in physiologically ordered N-R naps, thus providing support to the sequential hypothesis in humans. In addition, we found a negative effect of rapid-eye-movements in R sleep on perceptual consolidation, highlighting the complex role of sleep stages in the balance to remember and to forget.

Two-day low-dose dexamethasone suppression test more accurate than overnight 1-mg in women taking oral contraceptives.

INTRODUCTION: Late-night salivary cortisol (LSaC) and 24-h urinary free cortisol measurement, and overnight 1-mg dexamethasone suppression test (1 mg-DST) are the first-line screening tests recommended for Cushing's syndrome. Through elevations in the level of cortisol-binding globulin, oral contraceptive agents lead to increases in the total plasma cortisol concentration, yielding false-positive 1 mg-DST results. OBJECTIVE: To compare the accuracy of the overnight 1-mg DST and two-day low-dose DST (2d-DST) in female volunteers taking combined oestrogen-progestin oral contraceptives (COCs). METHODS: This prospective study enrolled 30 healthy participants. Their plasma cortisol response levels were compared after the 1-mg DST and 2d-DST and classified into three categories: normal (≤50 nmol/L), doubtful (51-138 nmol/L) and abnormal (>138 nmol/L). Salivary cortisol was also measured at late night and after the DSTs. RESULTS: Following the 1-mg DST and 2d-DST, the plasma cortisol concentrations decreased to a median of 69 nmol/L and 37 nmol/L, respectively (p < 0.001). A statistically significant higher proportion of unclear or abnormal results were observed after the 1-mg DST (63%) than after the 2d-DST (27%) (p = 0.004). None of the values were >138 nmol/L after the 2d-DST, while 11% of them were abnormal after the 1-mg DST (p = 0.25). No LSaC value was abnormal. CONCLUSION: Our results suggest that, when late-night salivary cortisol is not available, the 2d-DST could be a better screening option than the 1-mg DST for women taking oral contraceptive agents who are reluctant to stop them. This finding requires confirmation in those with a suspicion of hypercortisolism.