Evidence of membranolytic targeting and intracellular citrullination in neutrophils isolated from patients with rheumatoid arthritis.

Anti-citrullinated protein autoantibodies (ACPA) are diagnostic for rheumatoid arthritis (RA). The antigens recognized by these autoantibodies are produced by protein arginine deiminases (PADs), particularly PAD4. However, it remains unknown why and how PAD4 causes this aberrant citrullination in RA. Here, we report that poly-perforin pores are present on freshly isolated neutrophils from RA patients, but not on healthy donor neutrophils. Neutrophils with perforin pores also contained intracellular citrullinated proteins in the region adjacent to the pores. This response was replicated in vitro by treating neutrophils with purified perforin, which generated intense dots of anti-perforin immunofluorescence, calcium influx, and intracellular citrullination. Extensive neutrophil killing in Felty's syndrome, an aggressive form of RA, correlated with particularly high ACPA, and PAD4 autoantibodies. In contrast, other forms of death, including NETosis, apoptosis, and pyroptosis, produced minimal citrullination. We conclude that neutrophil targeting by perforin leading to intracellular citrullination takes place in patients with RA.

Type II innate lymphoid cell plasticity contributes to impaired reconstitution after allogeneic hematopoietic stem cell transplantation.

Type II innate lymphoid cells (ILC2s) maintain homeostasis and barrier integrity in mucosal tissues. In both mice and humans, ILC2s poorly reconstitute after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Determining the mechanisms involved in their impaired reconstitution could improve transplant outcomes. By integrating single-cell chromatin and transcriptomic analyses of transplanted ILC2s, we identify a previously unreported population of converted ILC1-like cells in the mouse small intestine post-transplant. Exposure of ILC2s to proinflammatory cytokines resulted in a mixed ILC1-ILC2 phenotype but was able to convert only a small population of ILC2s to ILC1s, which were found post-transplant. Whereas ILC2s protected against acute graft-versus-host disease (aGVHD) mediated mortality, infusion of proinflammatory cytokine-exposed ILC2s accelerated aGvHD. Interestingly, murine ILC2 reconstitution post-HSCT is decreased in the presence of alloreactive T cells. Finally, peripheral blood cells from human patients with aGvHD have an altered ILC2-associated chromatin landscape compared to transplanted controls. These data demonstrate that following transplantation ILC2s convert to a pro-pathogenic population with an ILC1-like chromatin state and provide insights into the contribution of ILC plasticity to the impaired reconstitution of ILC2 cells, which is one of several potential mechanisms for the poor reconstitution of these important cells after allo-HSCT.

Economic burden due to COVID-19 in a Colombian Caribbean state, 2020 and 2021.

OBJECTIVE: To estimate the economic burden associated with COVID-19 in Córdoba, Colombia, 2020 and 2021. METHODS: Economic burden study. Direct costs were analyzed from the third-party payer perspective using healthcare administrative databases and interviews from a cohort of confirmed COVID-19 cases from Córdoba. Costing aggregation was performed by the bottom-up method. Indirect costs were estimated using the productivity loss approach. Contrast tests and statistical models were estimated at 5% significance. RESULTS: We studied 1,800 COVID-19 cases. The average economic cost of COVID-19 per episode was estimated at US$ 2,519 (95%CI 1,980;3,047). The direct medical cost component accounted for 92.9% of the total; out-of-pocket and indirect costs accounted for 2% and 5.1%, respectively. CONCLUSION: COVID-19 economic cost was mainly due to direct medical costs. This study provided evidence of the economic burden faced by households due to COVID-19, with the most vulnerable households bearing much of the burden on their income.

Immediate Impacts of Wildfires on Ground-dwelling macroinvertebrate Communities under Stones in Mediterranean Oak Forests.

Wildfires are considered a major disturbance to forest ecosystems in the Mediterranean countries of Southern Europe. Although ground-dwelling macroinvertebrates are crucial to many soil functions, there is a fundamental lack of understanding of how wildfires impact this community in the immediate term and of the role of stones in their survival. Hence, in the present study we assessed the immediate effects of wildfires in the ground-dwelling macroinvertebrate community found under stones by comparing communities in burnt and non-burnt Mediterranean oak forests. Our results revealed that stones allowed the survival of many taxa in the burnt area. However, abundance, richness, diversity, and equitability per stone were significantly lower at the burnt than unburnt sites. Furthermore, the results also showed that richness and abundance increased significantly with increasing stone depth and area, both at the burnt and unburnt sites. Significant changes at the trophic level were observed in the burnt area comparing to the unburnt, particularly a decline in predators. No significant differences were identified concerning habitat associations among taxa. Overall, this study stressed the role of stones as microhabitats and refuge for the ground-dwelling macroinvertebrate community during wildfires.

Piloting a new cross-sector model of care to support parents with cancer: feasibility and acceptability of the Parent Support Worker role.

PURPOSE: A new Parent Support Worker (PSW) service was piloted in three Australian hospitals. This study assesses the feasibility and acceptability (including preliminary effectiveness) of the service in supporting cancer patients with children. METHODS: A multi-site, mixed-methods study collected quantitative and qualitative data on the effectiveness of the service (pre post-test, n = 36), qualitative and quantitative data on acceptability of the service (survey, n = 43), and qualitative data on acceptability (semi-structured interviews, n = 13). Feasibility was assessed through rates of service uptake amongst referred parents. RESULTS: Of 1133 parents referred, 810 (71%) accepted to receive the service, suggesting high interest in PSW support. Interviewees likewise reported that the service was accessible and facilitated further referrals, indicating good feasibility. Surveys completed three months after accessing PSW support showed high acceptability and satisfaction. Additionally, there was preliminary evidence of service impacts: parents' distress, parenting concerns, parenting efficacy, and stress about situations of concern improved significantly from pre- to post-service (all p < 0.005). Interviewees further described how their emotional coping and confidence to support and communicate with their children had improved through contact with the service. CONCLUSION: The PSW service, integrated into a novel cross-sector model of care, showed to be feasible and acceptable to parent patients and their partners and improved psychological and parenting outcomes. The study suggests refinements to the service and the need for future larger studies to explore the effectiveness of the service in improving parents' outcomes. This study complements previous evidence on the implementation of the PSW service in hospitals.

Endothelial Cell Derived Extracellular Vesicles and Hematopoiesis.

Extracellular vesicles (EVs) have been recognized as a novel way of cell-to-cell communication in the last several decades. It is believed that EVs exert their functions on nearby or distant cells through transfer of the cargo that they carry. In this review, we focus on EVs produced by endothelial cells, with emphasis on their role in hematopoiesis. We first describe how endothelial cells interact with hematopoietic stem/progenitor cells during development and in disease conditions. We then discuss EVs, ranging from their subtypes to isolation methods and analysis of EVs. With the above background information, we next review the literature related to endothelial cell derived EVs (ECEVs), including physiological functions and their clinical uses. In the last sections, we summarize the current results about the effect of ECEVs on hematopoiesis under physiological and stress conditions.

Feasibility and acceptability of an integrated mind-body intervention for depression: whole-body hyperthermia (WBH) and cognitive behavioral therapy (CBT).

OBJECTIVE: To examine the feasibility of an integrated mind-body MDD treatment combining cognitive behavioral therapy (CBT) and whole-body hyperthermia (WBH). METHODS: In this single-arm trial, 16 adults with MDD initially received 8 weekly CBT sessions and 8 weekly WBH sessions. Outcomes included WBH sessions completed (primary), self-report depression assessments completed (secondary), and pre-post intervention changes in depression symptoms (secondary). We also explored changes in mood and cognitive processes and assessed changes in mood as predictors of overall treatment response. RESULTS: Thirteen participants (81.3%) completed ≥ 4 WBH sessions (primary outcome); midway through the trial, we reduced from 8 weekly to 4 bi-weekly WBH sessions to increase feasibility. The n = 12 participants who attended the final assessment visit completed 100% of administered self-report depression assessments; all enrolled participants (n = 16) completed 89% of these assessments. Among the n = 12 who attended the final assessment visit, the average pre-post-intervention BDI-II reduction was 15.8 points (95% CI: -22.0, -9.70), p = 0.0001, with 11 no longer meeting MDD criteria (secondary outcomes). Pre-post intervention improvements in negative automatic thinking, but not cognitive flexibility, achieved statistical significance. Improved mood from pre-post the initial WBH session predicted pre-post treatment BDI-II change (36.2%; rho = 0.60, p = 0.038); mood changes pre-post the first CBT session did not. LIMITATIONS: Small sample size and single-arm design limit generalizability. CONCLUSION: An integrated mind-body intervention comprising weekly CBT sessions and bi-weekly WBH sessions was feasible. Results warrant future larger controlled clinical trials.Clinivaltrials.gov Registration: NCT05708976.

Human-Deer Relations during Late Prehistory: The Zooarchaeological Data from Central and Southern Portugal in Perspective.

Human-animal relations have been a fruitful research topic worldwide. The importance of deer in hunter-gatherer societies is undeniable, with cervids being commonly found in archaeological and past artistic records, with a notable amount of information recovered in the Iberian Peninsula. This relevance continues during Late Prehistory, but the attempt to discuss cervids under broader perspectives and based on different types of data is not as common. We intend to approach human-deer relations in Central and Southern Portuguese Late Prehistory by considering the zooarchaeological records, both deer abundance in faunal spectra and their presence in "meaningful" assemblages and structured depositions, as well as the use of deer and deer body parts in other socio-cultural and ideological practices. The synthesis of available data shows that human-deer relations changed through time and space, with different abundances related to hunting depending on chronology and geography. The use of deer or their body parts as a resource of symbolic nature also varied, being included in food-sharing events, offerings, structured depositions, and graphic representations. Changeability is part of the different relationships, ontologies, and cosmogonies that humans and deer developed in the Late Prehistoric relational world.

Development and performance evaluation of a qPCR-based assay for the fully automated detection of group B Streptococcus (GBS) on the Panther Fusion Open Access system.

Streptococcus agalactiae [group B Streptococcus (GBS)] poses a major threat as the primary cause of early-onset neonatal invasive disease, particularly when mothers are colonized rectovaginally. Although culture remains the gold standard for antepartum GBS screening, quantitative polymerase chain reaction (qPCR) offers advantages in terms of sensitivity and turnaround time. The aim of this study was to validate the clinical utility of an automated qPCR laboratory-developed test (LDT) for antepartum GBS screening using the Panther Fusion Open Access system (Hologic, California, USA). The LDT targeted a conserved region of the GBS surface immunogenic protein gene, demonstrating no cross-reactivity and high coverage (99.82%-99.99%). The limit of detection (LoD) was 118 CFU/mL. Comparison with commercial qPCR assays (Panther Fusion GBS and VIASURE Streptococcus B Real-Time) revealed an overall agreement of 99.7%, with a robust Cohen's kappa coefficient of 0.992. Testing of 285 rectovaginal swabs from pregnant women and 15 external quality assessment samples demonstrated exceptional diagnostic performance of the LDT, achieving a diagnostic sensitivity and specificity of 100%, underscoring its accuracy. Prevalence and predictive values were also determined to reinforce test reliability. Our research highlights the limitations of culture-based screening and supports the suitability of our qPCR-based LDT for GBS detection in a clinical setting.IMPORTANCERectovaginal colonization by GBS is a major risk factor for early-onset invasive neonatal disease. The most effective approach to reducing the incidence of early-onset disease (EOD) has been described as universal screening, involving assessment of GBS colonization status in late pregnancy and intrapartum antibiotic prophylaxis. Despite its turnaround time and sensitivity limitations, culture remains the gold standard method for GBS screening. However, nucleic acid amplification-based tests, such as qPCR, have been utilized due to their speed and high sensitivity and specificity. This study validated the clinical usefulness of an automated qPCR-LDT for antepartum GBS screening through the Panther Fusion Open Access system (Hologic). Our study addresses the critical need for more robust, sensitive, and rapid strategies for GBS screening in pregnant women that could favorably impact the incidence of EOD.

Coastal Mussel (Mytilus spp.) Soft Tissues as Bioindicators of Methylmercury: Exploring the Relationship Between Condition Index and Methylmercury Concentrations.

We investigated total mercury (THg) and methylmercury (MeHg) concentrations in coastal mussels (Mytilus spp.) sampled from the Minas Basin, Bay of Fundy and evaluated the relationship with condition index (CI). THg concentrations were low in sediment (mean THg = 5.15 ± 2.11 ng/g dw; n = 6) and soft tissues (mean THg = 62.3 ± 13.7 ng/g; mean MeHg = 13.2 ± 6.3 ng/g; n = 57). The THg in tissues had no significant relationship with CI (Rs= -0.205, p = 0.126). MeHg in tissues were significantly and negatively correlated with condition index (Rs = -0.361, p = 0.006) indicating that healthier mussels (higher CI) have lower mercury content possibly due to elimination strategies or growth dilution.

Tuberculosis patients face high treatment support costs in Colombia, 2021.

OBJECTIVE: To estimate the baseline to measure one of the three indicators of the World Health Organization (WHO) End TB strategy (2015-2035), measure the costs incurred by patients affected by tuberculosis (TB) during a treatment episode and estimate the proportion of households facing catastrophic costs (CC) and associated risk factors, in Colombia, 2021. MATERIAL AND METHODS: A nationally representative cross-sectional survey was conducted among participants on TB treatment in Colombia, using telephone interviews due to the exceptional context of the COVID-19 pandemic. The survey collected household costs (direct [medical and non-medical out-of-pocket expenses] and indirect) over an episode of TB, loss of time, coping measures, self-reported income, and asset ownership. Total costs were expressed as a proportion of annual household income and analyzed for risk factors of CC (defined as costs above 20% annual household income). RESULTS: The proportion of TB-affected households incurring in costs above 20% annual household income (CC) was 51.7% (95%CI: 45.4-58.0) overall, 51.3% (95%CI: 44.9-57.7) among patients with drug-sensitive (DS) TB, and 65.0% (95%CI: 48.0-82.0) among drug-resistant (DR). The average patient cost of a TB case in Colombia was $1,218 (95%CI 1,106-1,330) including $860.9 (95%CI 776.1-945.7) for non-medical costs, $339 (95%CI 257-421) for the indirect costs, and $18.1 (95%CI 11.9-24.4) for the medical costs. The factors that influenced the probability of facing CC were income quintile, job loss, DR-TB patient, and TB type. CONCLUSION: Main cost drivers for CC were non-medical out-of-pocket expenses and income loss (indirect costs). Current social protection programs ought to be expanded to mitigate the proportion of TB-affected households facing CC in Colombia, especially those with lower income levels.

Biochemical and toxicological profiles of venoms from an adult female South American bushmaster (Lachesis muta rhombeata) and her offspring.

In this work, we compared the biochemical and toxicological profiles of venoms from an adult female specimen of Lachesis muta rhombeata (South American bushmaster) and her seven offspring born in captivity, based on SDS-PAGE, RP-HPLC, enzymatic, coagulant, and hemorrhagic assays. Although adult and juvenile venoms showed comparable SDS-PAGE profiles, juveniles lacked some chromatographic peaks compared with adult venom. Adult venom had higher proteolytic (caseinolytic) activity than juvenile venoms (p < 0.05), but there were no significant inter-venom variations in the esterase, PLA2, phosphodiesterase and L-amino acid oxidase (LAAO) activities, although the latter activity was highly variable among the venoms. Juveniles displayed higher coagulant activity on human plasma, with a minimum coagulant dose ∼42% lower than the adult venom (p < 0.05), but there were no age-related differences in thrombin-like activity. Adult venom was more fibrinogenolytic (based on the rate of fibrinogen chain degradation) and hemorrhagic than juvenile venoms (p < 0.05). The effective dose of Bothrops/Lachesis antivenom (produced by the Instituto Butantan) needed to neutralize the coagulant activity was ∼57% greater for juvenile venoms (p < 0.05), whereas antivenom did not attenuate the thrombin-like activity of juvenile and adult venoms. Antivenom significantly reduced the hemorrhagic activity of adult venom (400 µg/kg, i. d.), but not that of juvenile venoms. Overall, these data indicate a compositional and functional ontogenetic shift in L. m. rhombeata venom.

Modeling the impact of high thermal conductivity paper on the performance and life of power transformers.

Degradation of insulation paper is a key contributor to the failure of power transformers. Insulation degradation accelerates at elevated temperatures, which highlights the potential for better thermal management to prolong life. While several studies have analyzed the benefits of high thermal conductivity oil for reducing temperatures inside a transformer, this study is an initial assessment of the benefits of high thermal conductivity paper on transformer life. Blending particulates with cellulosic fibers offers a pathway for high thermal conductivity paper (with good dielectric properties), which can reduce internal temperatures. Presently, life extensions that can be achieved by the use of such thermally conducting papers were estimated, with the thermal conductivity of the paper being the key parameter under study. The analytical-numerical thermal model used in this study was validated against experimental measurements in a distribution transformer, adding confidence to the utility of the model. This model was then used to provide estimates of hot-spot temperature reduction resulting from the use of papers with higher thermal conductivity than baseline. Transformer life was predicted conventionally by tracking the degree of polymerization of paper over time, based on an Arrhenius model. Results indicate that increasing the thermal conductivity of paper from 0.2 W/mK (baseline) to 1 W/mK reduces the hot spot temperature by 10 °C. While degradation significantly depends on the moisture and oxygen content, the model shows that such a temperature reduction can increase life for all conditions, by as much as a factor of three.

C4 Phosphoenolpyruvate Carboxylase: Evolution and transcriptional regulation.

Photosynthetic phosphoenolpyruvate carboxylase (PEPC) catalyses the irreversible carboxylation of phosphoenolpyruvate (PEP), producing oxaloacetate (OAA). This enzyme catalyses the first step of carbon fixation in C4 photosynthesis, contributing to the high photosynthetic efficiency of C4 plants. PEPC is also involved in replenishing tricarboxylic acid cycle intermediates, such as OAA, being involved in the C/N balance. In plants, PEPCs are classified in two types: bacterial type (BTPC) and plant-type (PTPC), which includes photosynthetic and non-photosynthetic PEPCs. During C4 evolution, photosynthetic PEPCs evolved independently. C4 PEPCs evolved to be highly expressed and active in a spatial-specific manner. Their gene expression pattern is also regulated by developmental cues, light, circadian clock as well as adverse environmental conditions. However, the gene regulatory networks controlling C4 PEPC gene expression, namely its cell-specificity, are largely unknown. Therefore, after an introduction to the evolution of PEPCs, this review aims to discuss the current knowledge regarding the transcriptional regulation of C4 PEPCs, focusing on cell-specific and developmental expression dynamics, light and circadian regulation, as well as response to abiotic stress. In conclusion, this review aims to highlight the evolution, transcriptional regulation by different signals and importance of PEPC in C4 photosynthesis and its potential as tool for crop improvement.

The effects of antibiotic exposures on the gut resistome during hematopoietic cell transplantation in children.

Antibiotic resistance is a global threat driven primarily by antibiotic use. We evaluated the effects of antibiotic exposures on the gut microbiomes and resistomes of children at high risk of colonization by antibiotic-resistant bacteria. We performed shotgun metagenomic sequencing of 691 serially collected fecal samples from 80 children (<18 years) undergoing hematopoietic cell transplantation. We evaluated the effects of aerobic (cefepime, vancomycin, fluoroquinolones, aminoglycosides, macrolides, and trimethoprim-sulfamethoxazole) and anaerobic (piperacillin-tazobactam, carbapenems, metronidazole, and clindamycin) antibiotic exposures on the diversity and composition of the gut microbiome and resistome. We identified 372 unique antibiotic resistance genes (ARGs); the most frequent ARGs identified encode resistance to tetracyclines (n = 88), beta-lactams (n = 84), and fluoroquinolones (n = 79). Both aerobic and anaerobic antibiotic exposures were associated with a decrease in the number of bacterial species (aerobic, ß = 0.71, 95% CI: 0.64, 0.79; anaerobic, ß = 0.66, 95% CI: 0.53, 0.82) and the number of unique ARGs (aerobic, ß = 0.81, 95% CI: 0.74, 0.90; anaerobic, ß = 0.73, 95% CI: 0.61, 0.88) within the gut metagenome. However, only antibiotic regimens that included anaerobic activity were associated with an increase in acquisition of new ARGs (anaerobic, ß = 1.50; 95% CI: 1.12, 2.01) and an increase in the relative abundance of ARGs in the gut resistome (anaerobic, ß = 1.62; 95% CI: 1.15, 2.27). Specific antibiotic exposures were associated with distinct changes in the number and abundance of ARGs for individual antibiotic classes. Our findings detail the impact of antibiotics on the gut microbiome and resistome and demonstrate that anaerobic antibiotics are particularly likely to promote acquisition and expansion of antibiotic-resistant bacteria.

The bHLH transcription factor OsPRI1 activates the Setaria viridis PEPC1 promoter in rice.

Photosynthetic efficiency is reduced by the dual role of Rubisco, which acts either as a carboxylase or as an oxygenase, the latter leading to photorespiration. C4 photosynthesis evolved as a carbon-concentrating mechanism to reduce photorespiration. To engineer C4 into a C3 plant, it is essential to understand how C4 genes, such as phosphoenolpyruvate carboxylase (PEPC1), are regulated to be expressed at high levels and in a cell-specific manner. Yeast one-hybrid screening was used to show that OsPRI1, a rice bHLH transcription factor involved in iron homeostasis, binds to the Setaria viridis PEPC1 promoter. This promoter drives mesophyll-specific gene expression in rice. The role of OsPRI1 in planta was characterized using a rice line harbouring SvPEPC1pro ::GUS. We show that OsPRI1 activates the S. viridis PEPC1 promoter by binding to an N-box in the proximal promoter, and that GUS activity is highly reduced in SvPEPC1pro ::GUS lines when OsPRI1 is mutated. Cross-species comparisons showed that the SvPRI1 homolog binds to the SvPEPC1 promoter but the maize ZmPRI1 does not bind to the ZmPEPC1 promoter. Our results suggest that elements of the iron homeostasis pathway were co-opted to regulate PEPC1 gene expression during the evolution of some but not all C4 species.

How Possible Is the Elimination of Viral Hepatitis? An Analysis Based on the Global Burden of Disease from Hepatitis B and C, 1990-2019.

This study assesses the feasibility of hepatitis B (HBV) and C (HCV) elimination using an analysis of trends of epidemiology data (1990-2019) from the Global Burden of Disease Study. Joinpoint regression analysis was used to identify significantly changing points in the trends of Age-standardized Prevalence Rates (ASPR) and Age-standardized Mortality Rates (ASMR) and to estimate the annual percentage changes (APC) and the average annual percentage changes (AAPC) for the period. The Sociodemographic Index (SDI) was used to analyze trends between countries. The total percentage change of the ASPR (2019/1990) was -31.4% and -12.8% for HBV and HCV worldwide, respectively; the rate ratio (HBV/HCV) was 2.5. Mortality had decreased for HBV but not for HCV. The total percentage change for the ASMR (2019/1990) was -26.7% and 10.0% for HBV and HCV, respectively. While the ASMR of HBV decreased, HCV increased during this period. The percentage change in ASMR of HBV was highest in countries with high-middle SDI and lowest in countries with high SDI. For HCV, the percentage change in ASMR was highest in countries with high SDI (increase), and only in countries with low SDI did it decrease. The global HBV and HCV rates have fallen with different AAPCs associated with the SDI. Despite the advances, there is still a long way to go to achieve the 2030 elimination goals. An important challenge is related to finding a way to speed up the yearly rate at which the decline is happening.

Preconditioning Frailty Phenotype Influences Survival and Relapse for Older Allogeneic Transplantation Recipients.

Hematologic malignancies disproportionately affect older adults. Hematopoietic cell transplantation (HCT) is potentially curative, but poor overall survival (OS) has limited its use in older adults. Fried's frailty phenotype (FFP) is a geriatric assessment tool that combines objective and subjective performance measures: gait speed, grip strength, activity level, exhaustion, and weight loss. People meeting ≥3 criteria are classified as frail; 1 or 2 criteria, as pre-frail; and 0 criteria, as fit. To evaluate the association of pre-HCT FFP with post-HCT outcomes, we assessed FFP prior to conditioning for 280 HCT recipients age ≥60 years with acute leukemia or a myeloid neoplasm at 3 institutions. When analyzing survival by age group, patients age ≥70 years had inferior OS compared to patients age 60 to 69 years (P = .002), with corresponding OS estimates of 38.9% (95% confidence interval [CI], 27.8% to 49.9%) and 59.3% (95% CI, 51.9% to 65.9%). Nonrelapse mortality (NRM) also was significantly higher in the older patients (P = .0005); the 2-year cumulative incidences of NRM were 38.5% (95% CI, 27.5% to 49.2%) and 17.2% (95% CI, 12.3% to 22.8%), for older and younger recipients, respectively. The cumulative incidences of relapse did not differ by age group (P = .3435). Roughly one-third (35.5%) of the patients were fit, 57.5% were pre-frail, and 7.5% were frail, with corresponding 2-year OS estimates of 68.4% (95% CI, 57.9% to 76.8%), 45.5% (95% CI, 37.4% to 53.2%), and 45.8% (95% CI, 23.4% to 65.8%) (P = .013). FFP was not significantly associated with NRM, but being frail or pre-frail was associated with a higher rate of disease-related deaths (33.3% and 27.3%, respectively, compared with 17.4% for fit patients; P = .043). In univariate modeling of restricted mean survival time with a 3-year horizon (RMST_3y), the factors that were significantly associated were FFP, age, Karnofsky Performance Status (KPS), Disease Risk Index (DRI), and HCT-specific Comorbidity Index (HCT-CI). Of those factors, only FFP (P = .006), age (P = .006), KPS (P = .004), and DRI (P = .005) were significantly associated in multivariate modeling of RMST_3y. Estimates of RMST_3y were computed and 5 risk-groups were created with survival ranging from 31.4 months for those who were age 60 to 69 years, fit, had KPS 90 to 100, and low/intermediate-risk DRI compared to 10.5 months for those who had high-risk features for all the evaluated factors. In univariate and multivariate analyses for restricted mean time to relapse with a 3-year horizon (RMRT_3y), FFP (pre-frail versus fit, P = .007; frail versus fit, P = .061) and DRI (P = .001) were the only significant factors. Predicted RMRT_3y was longest (30.6 months) for those who were fit and had low/intermediate-risk DRI scores and shortest (19.1 months) for those who were frail and had high-risk or very high-risk DRI scores. Both age and FFP impact survival after HCT. Incorporation of FFP into pre-HCT evaluations may improve decision-making and counseling regarding HCT risk for older adults. Our findings support future trials designed to reverse frailty, such as pre-HCT supervised exercise programs, and correlative analyses to unravel the connection of frailty and relapse to generate future targets for intervention. Finally, exploration of novel HCT platforms to reduce relapse in pre-frail and frail patients, as well as reduce NRM in adults age >70 years, are warranted.

Test-retest reliability of Bayesian estimations of the effects of stimulation, prior information and individual traits on pain perception.

BACKGROUND: There is inter-individual variability in the influence of different components (e.g. nociception and expectations) on pain perception. Identifying the individual effect of these components could serve for patient stratification, but only if these influences are stable in time. METHODS: In this study, 30 healthy participants underwent a cognitive pain paradigm in which they rated pain after viewing a probabilistic cue informing of forthcoming pain intensity and then receiving electrical stimulation. The trial information was then used in a Bayesian probability model to compute the relative weight each participant put on stimulation, cue, cue uncertainty and trait-like bias. The same procedure was repeated 2 weeks later. Relative and absolute test-retest reliability of all measures was assessed. RESULTS: Intraclass correlation results showed good reliability for the effect of the stimulation (0.83), the effect of the cue (0.75) and the trait-like bias (0.75 and 0.75), and a moderate reliability for the effect of the cue uncertainty (0.55). Absolute reliability measures also supported the temporal stability of the results and indicated that a change in parameters corresponding to a difference in pain ratings ranging between 0.47 and 1.45 (depending on the parameters) would be needed to consider differences in outcomes significant. The comparison of these measures with the closest clinical data we possess supports the reliability of our results. CONCLUSIONS: These findings support the hypothesis that inter-individual differences in the weight placed on different pain factors are stable in time and could therefore be a possible target for patient stratification. SIGNIFICANCE: Our results demonstrate the temporal stability of the weight healthy individuals place on the different factors leading to the pain response. These findings give validity to the idea of using Bayesian estimations of the influence of different factors on pain as a way to stratify patients for treatment personalization.