Operational tolerance after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear which cellular and molecular pathways ...are driving tolerance in these patients. We performed genome-wide analysis of DNA methylation in peripheral blood mononuclear cells from kidney transplant recipients with chronic rejection and operational tolerance from the Genetic Analysis of Molecular Biomarkers of Immunological Tolerance (GAMBIT) study. Our results showed that both clinical stages diverge in 2737 genes, indicating that each one has a specific methylation signature associated with transplant outcome. We also observed that tolerance is associated with demethylation in genes involved in immune function, including B and T cell activation and Th17 differentiation, while in chronic rejection it is associated with intracellular signaling and ubiquitination pathways. Using co-expression network analysis, we selected 12 genomic regions that are specifically hypomethylated or hypermethylated in tolerant patients. Analysis of these genes in transplanted patients with low dose of steroids showed that these have a similar methylation signature to that of tolerant recipients. Overall, these results demonstrate that methylation analysis can mirror the immune status associated with transplant outcome and provides a starting point for understanding the epigenetic mechanisms associated with tolerance.
Forest dieback and mortality episodes triggered by droughts are receiving increasing attention due to the projected increases in these extreme climate events. However, the role played by nutrient ...impairment in dieback is understudied, despite interactions among carbon-water balances and nutrition. Here, we followed a comparative analysis of long-term growth, intrinsic water-use efficiency (iWUE), oxygen isotopes (δ18O) and wood-nutrient composition patterns between living (L) and dead (D) trees of a Nothofagus dombeyi population, showing dieback in Argentina. The onset of the growth decline of D trees occurred ca. 40 years before death. These trees showed higher iWUE, pointing to higher drought stress. Their lower δ18O values, together with the uncoupling between δ18O and leaf-level processes, suggested a deeper source of water uptake for this vigor class. D trees showed a poorer nutritional status than L trees that likely amplified the dieback. This was supported by numerous positive associations of P- and K-concentrations in wood and related ratios with iWUE, δ18O and tree growth. Therefore, drought-related nutrient deterioration can significantly contribute to dieback and be an early warning signal of impending tree death.
INTRODUCTION During the past two years, sixteen institutions members of the Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC) have undertaken a multicenter and prospective study ...with the purpose of evaluating the frailty of adults' candidates to autologous HCT (auto-HCT) and of investigating the effect of frailty in transplant outcomes. METHODS All patients consulted for auto-HCT were eligible to be included in the study after providing informed consent. Frailty was evaluated at first consultation, at admission, and after the stem cell infusion, using the HCT Frailty Scale (Salas et al. BMT 2023), designed classify candidates for allogeneic HCT into fit, pre-frail and frail categories ( Table 1). The frailty assessment was made by the hematologists and nurses team as part of the clinical practice and utilizing existing resources. The median time to complete the evaluation ranged from 8 to 10 minutes. As an extension, this study includes the evaluation of patient´s quality of life (QoL) using the EQ-5D-EL questionnaire. QoL was measured at HCT admission and day +100 after the stem cell infusion. This study has no external funding. The results obtained from the frailty assessment were not used to determine HCT eligibility and/or to design the HCT process. RESULTS This study includes 380 consecutive adult candidates for auto-HCT who have been evaluated for frailty in the sixteen participating institutions between February 2021 and May 2023. Overall, the median age was 58 (range, 18-76) and 219 (57.6%) were males. Multiple myeloma or other plasma cell discrasias (PCD) (n=213, 62.1%) and lymphoproliferative disorders (SLP) (n=121, 31.8%) were the most prevalent baseline diagnosis. Prior to auto-HCT, 104 (33.8%) out of 307 adults had an KPS<90% and 35 (12.4%) out of 282 an HCT-CI>3. All patents included underwent their auto-HCT during the study period, and in only 20 (5.3%) of the cases, the standard doses of the conditioning regimen were required to be adjusted secondary to the patient´s condition, age or comorbidities. The first consultation was mostly performed before the stem cell collection. At first consultation, 108 (28.4%) adults were classified as fit, 203 (53.4%) as pre-frail, and 69 (18.2%) as frail. Frail patients were more likely to be older than 60 (OR 5.3, p<0.001), to have a KPS<90% (HR 5.80, p<0.01), and an abnormal Mini-Cog test (<3) (OR 5.81, p=0.0271). The probability of being frail was not affected by sex (HR 1.7, p=0.173), comorbidities (HCT-CI>3) (p=0.196), or underlying diagnosis (multivariate binary regression analysis). Frailty at first consultation was not associated with a more prolonged HCT hospitalization (p=0.663) or higher readmissions (p=0.579). However, a non-significant trend to lower OS was observed in frail patients undergoing auto-HCT than in the rest 1-year OS of fit, pre-frail, and frail adults: 98.5%, 95.6%, and 84.4% (p=0.072) ( Table 1). The impact of frailty in QoL was also investigated. As shown in Table 2, compared with fit patients, pre-frail and frail adults had worse score values throughout all the variables included questionnaire. Since PCD and SLP are the most prevalent indications for auto-HCT, trends on frailty were investigated separately on these subgroups of patients . Trends on frailty were examined and reported in Table 1. At first consultation, the proportions of fit, pre-frail, and frail adults were similar between the two groups (p=0.896). At HCT admission, the proportion of frail patients with PCD tend to be higher than in the other group (16.6% vs.9.9%, p=0.051). Nevertheless, at day +100, frailty stages were again similar between the two study groups. Lastly, when the impact of frailty in OS was investigated in these two subgroups of patients, the negative effect of this syndrome in post-transplant outcomes was only observed in patients with PCD (p=0.012). CONCLUSIONS This study validates the applicability of the HCT Frailty Scale in adult candidates for auto-HCT. At first consultation, frailty had an incidence of 18% being more prevalent in older adults and with worse performance status. Moreover, it´s presence during the post-transplant process was associated with worse QoL. Preliminary data shows that frailty at first consultation correlates with lower OS in patients with PCD. Further analyses will be conducted to better investigate this result.
INTRODUCTION Including frailty in the evaluation of patients before HCT is recommended, but more needs to be done to reach a consensus on how to evaluate and manage this syndrome in clinical ...practice. Since 2021, sixteen institutions members of the Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC) have participated in a multicenter and prospective study with the purpose of investigating the state of frailty of adult patient candidates to HCT and evaluate the effect of frailty in transplant outcomes. METHODS All Spanish institutions members of the Group were invited to participate in the study and finally 16 of them were actively involved in it. All patient candidates for HCT were eligible to be included in the study after providing informed consent. Frailty was evaluated at first consultation, at admission, and after the stem cell infusion, using the HCT Frailty Scale (Salas et al. BMT 2023) as described in Table 1. According to their respective total frailty score, patients were classified into three levels of frailty: fit, pre-frail, and frail. The frailty assessment was made by the hematologists and nurse team as part of the clinical practice, utilizing existing human resources and without requiring additional medical appointments for patients. The median time to complete the evaluation ranged from 8 to 10 minutes. The evaluation of physical frailty was complemented with the Mini-Cog test. The results obtained from the frailty assessment were not used to determine HCT eligibility and/or to design the HCT process. This study did not have external funding. RESULTS Between February 2021 and May 2023, 916 consecutive adult candidates for HCT in any of the participating institutions were included in the project. Of all of them, the results reported here correspond only to the 341 adult candidates for allogeneic (allo)-HCT. Median patients' age was 56 (range, 18-76); 65.3% were males; the most prevalent baseline diagnosis was myeloid malignancies (57.5%). Prior to HCT, 36.8% adults had an KPS<90% and 11.5% an HCT-CI>3, 53.1% patients received reduced intensity conditioning regimens, 25.5% alternative donor grafts, and 61.6% received PTCY-based prophylaxis. At the first consultation, 94 (27.6%) adults were classified as fit, 203 (59.5%) as pre-frail, and 44 (12.9%) as frail. Frail patients were more likely to have a KPS<90% (OR 2.80, p<0.01) and an abnormal result of the Mini-Cog test (<3) (OR 8.21, P<0.001). The probability of being frail was independent of age (continuous) (p=0.654), sex (p=0.323), and comorbidities (HCT-CI>3) (p=0.196) (multivariate binary regression analysis). As shown in Table 1, the state of frailty changed throughout the study period, confirming the dynamic nature of the frailty syndrome. A total of 59 (17.3%) patients went through a pre-transplant rehabilitation (pre-hab) program. With this information, the dynamics of frailty of these patients was compared with that of patients who did not join a pre-hab program. At HCT admission, the distribution of patients across the frailty categories was different between the two groups (p=0.028). The proportion of fit patients was higher in the pre-hab group (55.1% vs. 26.7%) because part of the pre-frail patients changed to the fit category. The power of the HCT Frailty Scale to predict OS was evaluated in the subsample of 216 patients that had a minimum follow-up of 120 days among survivors. Table 1 shows that the probability of OS at 1-year increases with the level of fitness of the patients at first consultation, as follows: 35.6% (frail), 70.5% (pre-frail) and 72% (fit), (p<0.001). Secondly, the effect of the level of fitness in the probability of 1-year OS was higher with frailty measured at the time of HCT admission; respectively, 20%, 66.8% and 78.9%. (p<0.001) ( Figure 1). The difference is explained by the improvement in fitness of the patients that participated in a pre-hab program between first consultation and admission. CONCLUSIONS This study validates the applicability of the HCT Frailty Scale at HCT institutions that are part of a health care system different from that where it was first implemented. The HCT Frailty Scale classifies adult patients to allo-HCT in three categories of frailty, frail that have predictive power over transplant outcomes. Frailty syndrome is independent of age and comorbidities and can be improved through pre-hab programs with the positive result of improving the OS of transplanted patients.
Drought‐induced episodes of tree mortality can determine forest dynamics and structure, particularly in forests dominated by single species. Short‐ and mid‐term climate projections indicate that ...strong changes in annual precipitation may strike more often in northern Patagonia. Data for recruitment, growth, and survival of Nothofagus dombeyi tree individuals were collected at several sites across the Nahuel Huapi National Park in Argentina. We combined mathematically all these different demographic stages into an Integral Projection Model to simulate 100‐yr projections of simulated stand structure under different frequencies of extreme drought episodes. We projected total basal area and the number of individuals for three different initial stand types (i.e., young, medium, and old) and for varying drought frequencies (i.e., from 1 to 5 drought events every 100 years). Recruitment into the dbh ≥ 10 cm size class under normal conditions (i.e., without drought) was higher than under episodic drought conditions. In addition, survival under normal conditions was higher than under drought conditions, especially for small trees. Differences in growth were also important, with trees growing more vigorously under normal than under drought conditions. Our simulations predicted that N. dombeyi populations would experience a reduction in tree density in the mid‐term if, as predicted by the IPCC projections, the frequency of future drought events increased. The simulations also showed that in those cases, young stands should suffer the most. Drought‐mediated changes may induce a decline in the development of N. dombeyi forests in the mid‐ and long term by a drastic reduction in tree density.
The cellular immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in response to full mRNA COVID-19 vaccination could be variable among healthy individuals. Studies based ...only in specific antibody levels could show an erroneous immune protection at long times. For that, we analyze the antibody levels specific to the S protein and the presence of SARS-CoV-2-specific T cells by ELISpot and AIM assays in intensive care unit (ICU) workers with no antecedents of COVID-19 and vaccinated with two doses of mRNA COVID-19 vaccines. All individuals were seronegative for the SARS-CoV-2 protein S before vaccination (Pre-v), but 34.1% (14/41) of them showed pre-existing T lymphocytes specific for some viral proteins (S, M and N). One month after receiving two doses of COVID-19 mRNA vaccine (Post-v1), all cases showed seroconversion with high levels of total and neutralizing antibodies to the spike protein, but six of them (14.6%) had no T cells reactive to the S protein. Specifically, they lack of specific CD8
T cells, but maintain the contribution of CD4
T cells. Analysis of the immune response against SARS-CoV-2 at 10 months after full vaccination (Post-v10), exhibited a significant reduction in the antibody levels (p<0.0001) and protein S-reactive T cells (p=0.0073) in all analyzed individuals, although none of the individuals become seronegative and 77% of them maintained a competent immune response. Thus, we can suggest that the immune response to SARS-CoV-2 elicited by the mRNA vaccines was highly variable among ICU workers. A non-negligible proportion of individuals did not develop a specific T cell response mediated by CD8
T cells after vaccination, that may condition the susceptibility to further viral infections with SARS-CoV-2. By contrast, around 77% of individuals developed strong humoral and cellular immune responses to SARS-CoV-2 that persisted even after 10 months. Analysis of the cellular immune response is highly recommended for providing exact information about immune protection against SARS-CoV-2.
One of the most extensive dendrochronological field collections in South America was conducted by LaMarche and collaborators from 1973 to 1978. However, no robust chronologies had been developed from ...these species and/or sites because there were not enough samples collected, or simply because the materials were never processed. Here, I report on results from a re-examination of all Nothofagus dombeyi samples collected during LaMarche and collaborators' field sampling in South America. A tree-ring chronology was developed for the Alto Vilches site in Chile. For the other sites sampled by LaMarche and collaborators, there were not enough samples, or series were not sufficiently long to build a chronology or to provide adequate information about tree growth. The Alto Vilches (VIL) chronology extends into the early 1800s, and shows high mean sensitivity values and a strong common signal. As expected, the VIL chronology evidenced narrow rings for several years that correspond with low precipitation periods in Patagonia. Making available the information kept in unprocessed tree-ring samples reinforces the dendrochronological potential of this species and strengthens chronology networks developed for ecological studies in northern Patagonia. Finally, this study honors the initial work of LaMarche and collaborators and provides closure to a small part of it.
Spatial proximity between different plant species could modify the sign (positive or negative) of plant–herbivore interaction. The chance of a plant being detected and colonized by herbivorous ...insects depends not only on the plant's own traits but also on the identity of the neighbouring plants that grow with it. The closest proximity between plants occurs in climbers and their host. We conducted a field experiment to assess the effect of spatial association between a climber plant, Vicia nigricans (Fabaceae), and two host shrubs, Berberis buxifolia (Berberidaceae) and Schinus patagonica (Anacardiaceae), on insect herbivory levels, reproductive output and growth. The presence and identity of the host shrubs affected the herbivory levels of the climber V. nigricans, but not the reproductive output. For the climber, the probability of being attacked by insects could depend on the characteristics of the host shrub. Taking the opposite perspective, climber association affected different traits of the host shrubs. The association with the climber decreased leaf damage (positive), tended to decrease leaf production (negative) and did not affect reproductive output (neutral). Our findings suggest that spatial association between plant species could change the sign of the interactions between plants and insects affecting different traits. By taking into account the perspective of both plants involved in the association, this study shows and emphasizes that plant–animal interactions strongly depend on the community context.
Considerable variability exists in the way health-care providers treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in Latin America. The most frequently used ...treatments for ANCA-associated vasculitis are cyclophosphamide and prolonged glucocorticoid tapers; however, randomised controlled trials conducted over the past 30 years have led to the development of several evidence-based treatment alternatives for these patients. Latin America faces socioeconomic challenges that affect access to care, and the use of certain costly medications with proven efficacy ANCA-associated vasculitis is often restricted. For these reasons, the Pan American League of Associations for Rheumatology developed the first ANCA-associated vasculitis treatment guidelines tailored for Latin America. A panel of local vasculitis experts generated clinically meaningful questions related to the treatment of ANCA-associated vasculitis using the Population, Intervention, Comparator, and Outcome (PICO) format. Following the Grading of Recommendations Assessment, Development, and Evaluation methodology, a team of methodologists conducted a systematic literature review. The panel of vasculitis experts voted on each PICO question and made recommendations, which required at least 70% agreement among the voting members. 21 recommendations and two expert opinion statements for the treatment of ANCA-associated vasculitis were developed, considering the current evidence and the socioeconomic characteristics of the region. These recommendations include guidance for the use of glucocorticoids, non-glucocorticoid immunosuppressants, and plasma exchange.
To describe maternal and neonatal outcomes in pregnant women undergoing hemodialysis in a referral center in Brazilian Southeast side.
Retrospective and descriptive study, with chart review of all ...pregnancies undergoing hemodialysis that were followed-up at an outpatient clinic of high- risk prenatal care in Southeast Brazil.
Among the 16 women identified, 2 were excluded due to follow-up loss. In 14 women described, hypertension was the most frequent cause of chronic renal failure (half of cases). The majority (71.4%) had performed hemodialysis treatment for more than one year and all of them underwent 5 to 6 hemodialysis sessions per week. Eleven participants had chronic hypertension, 1 of which was also diabetic, and 6 of them were smokers. Regarding pregnancy complications, 1 of the hypertensive women developed malignant hypertension (with fetal growth restriction and preterm delivery at 29 weeks), 2 had acute pulmonary edema and 2 had abruption placenta. The mode of delivery was cesarean section in 9 women (64.3%). All neonates had Apgar score at five minutes above 7.
To improve perinatal and maternal outcomes of women undergoing hemodialysis, it is important to ensure multidisciplinary approach in referral center, strict control of serum urea, hemoglobin and maternal blood pressure, as well as close monitoring of fetal well-being and maternal morbidities. Another important strategy is suitable guidance for contraception in these women.
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