Long-term survival after unrelated donor marrow transplantation for aplastic anaemia after optimized conditioning regimen: a retrospective multicentre cohort study.

Background: Almost all acquired severe aplastic anaemia is immune mediated and characterised by hypocellular bone marrow and ≥2 affected haematopoietic lineages. The optimal preparartive regimen for unrelated donor transplantation remains to be established. We aimed to study long-term outcomes after unrelated donor transplantation for severe aplastic anaemia with de-escalation of cyclophosphamide (Cy) dose in steps of 50 mg/kg (150, 100, 50, 0 mg/kg) in combination with total body irradiation (TBI) 2 Gy, anti-thymocyte globulin (ATG) and fludarabine. Methods: Ninety-six patients with severe aplastic anaemia aged ≤65 years with adequate organ function enrolled on a trial of human leukocyte antigen (HLA)-matched or 1 HLA-locus mismatched unrelated donor marrow transplantation conducted between 02/2006 and 12/2013 in the United States (NCT00326417). Exclusion criteria were Karnofsky performance status of less than 60, clonal cytogenetic abnormalities and inherited marrow failure syndormes. The primary outcome was day-100 engraftment (achievement of absolute neutrophil recovery to at least 0.5 × 109/L without subsequent decline) and day-100 survival. The trial determined the lowest effective Cy dose as 50 mg/kg (n = 38) for day-100 engraftment and survival. Cy dose 100 mg/kg (n = 41) was also acceptable. Accrual to Cy doses 150 mg/kg (n = 15) and 0 mg/kg (n = 3) was terminated early for toxicities. The current study is an extended follow up of patients enrolled on the trial (NCT00326477) and includes 76 of 96 patients alive ≥1 year after transplantation. There were 20 deaths in the first year after transplantation (Cy 0 mg/kg [n = 2], Cy 50 mg/kg [n = 1], Cy 100 mg/kg [n = 10], Cy 150 mg/kg [n = 7]). Patients were followed prospectively from transplantation and data reported using standardized data collection forms until death, loss to follow up or last contact through November 2023. The incidence of graft failure was calculated using the cumulative incidence estimator and the probability of survival using the Kaplan-Meier estimator. Findings: The median follow up of the cohort is 8.02 (IQR) 5.16-10.12) years. With Cy 50 mg/kg, there was one graft failure and five deaths ≥1 year after transplantation. With Cy 100 mg/kg there was only one late death and no graft failure. The 8-year probabilities of survival were 85.0% (95% CI 67.3-93.5) and 75.6% (95% CI 59.4-86.1) after Cy 50 mg/kg and 100 mg/kg, respectively, P = 0.31. With Cy 0 mg/kg and 150 mg/kg, there were no graft failures or death ≥1 year after transplantation. Regardless of Cy dose 12 of 15 patients aged ≥50 years died. Interpretation: Cy 50 mg/kg or 100 mg/kg with TBI 2 Gy, ATG and fludarabine are effective conditioning regimens for unrelated donor marrow transplants for aplastic anaemia. Identification of an optimized transplantation approach for patients aged ≥50 years is needed. Funding: US National Institutes of Health.

Alternating magnetic fields (AMF) and linezolid reduce Staphylococcus aureus biofilm in a large animal implant model.

OBJECTIVES: We aimed to evaluate the effectiveness of alternating magnetic fields (AMF) combined with antibiotics in reducing Staphylococcus aureus biofilm on metal implants in a large animal model, compared to antibiotics alone. METHODS: Metal plates were inoculated with a clinical MRSA strain and then implanted into thirty-three ewes divided into three groups: positive control, linezolid only, and a combination of linezolid and AMF. Animals had either titanium or cobalt-chrome plates and were sacrificed at 5 or 21 days post-implantation. Blood and tissue samples were collected at various time points post-AMF treatment. RESULTS: In vivo efficacy studies demonstrated significant biofilm reduction on titanium and cobalt-chrome implants with AMF-linezolid combination treatment compared to controls. Significant bacterial reductions were also observed in surrounding tissues and bones. Cytokine analysis showed improved inflammatory responses with combination therapy, and histopathology confirmed reduced inflammation, necrosis, and bacterial presence, especially at 5 days post-implantation. CONCLUSIONS: This study demonstrates that combining AMF with antibiotics significantly reduces biofilm-associated infections on metal implants in a large animal model. Numerical simulations confirmed targeted heating, and in vivo results showed substantial bacterial load reduction and reduced inflammatory response. These findings support the potential of AMF as a non-invasive treatment for prosthetic joint infections.

Effects of Schistosoma haematobium infection and treatment on the systemic and mucosal immune phenotype, gene expression and microbiome: A systematic review.

BACKGROUND: Urogenital schistosomiasis caused by Schistosoma haematobium affects approximately 110 million people globally, with the majority of cases in low- and middle-income countries. Schistosome infections have been shown to impact the host immune system, gene expression, and microbiome composition. Studies have demonstrated variations in pathology between schistosome subspecies. In the case of S. haematobium, infection has been associated with HIV acquisition and bladder cancer. However, the underlying pathophysiology has been understudied compared to other schistosome species. This systematic review comprehensively investigates and assimilates the effects of S. haematobium infection on systemic and local host mucosal immunity, cellular gene expression and microbiome. METHODS: We conducted a systematic review assessing the reported effects of S. haematobium infections and anthelmintic treatment on the immune system, gene expression and microbiome in humans and animal models. This review followed PRISMA guidelines and was registered prospectively in PROSPERO (CRD42022372607). Randomized clinical trials, cohort, cross-sectional, case-control, experimental ex vivo, and animal studies were included. Two reviewers performed screening independently. RESULTS: We screened 3,177 studies and included 94. S. haematobium was reported to lead to: (i) a mixed immune response with a predominant type 2 immune phenotype, increased T and B regulatory cells, and select pro-inflammatory cytokines; (ii) distinct molecular alterations that would compromise epithelial integrity, such as increased metalloproteinase expression, and promote immunological changes and cellular transformation, specifically upregulation of genes p53 and Bcl-2; and (iii) microbiome dysbiosis in the urinary, intestinal, and genital tracts. CONCLUSION: S. haematobium induces distinct alterations in the host's immune system, molecular profile, and microbiome. This leads to a diverse range of inflammatory and anti-inflammatory responses and impaired integrity of the local mucosal epithelial barrier, elevating the risks of secondary infections. Further, S. haematobium promotes cellular transformation with oncogenic potential and disrupts the microbiome, further influencing the immune system and genetic makeup. Understanding the pathophysiology of these interactions can improve outcomes for the sequelae of this devastating parasitic infection.

Treatment outcomes following partial shave biopsy of atypical and malignant melanocytic tumors in pediatric patients.

Pediatric melanoma is the most common skin cancer in children and treatment relies on accurate staging. The American Academy of Dermatology recommends excisional biopsy for suspicious skin lesions, however, partial shave biopsies are often performed, the impact of which is unknown in pediatric and adolescent/young adult (AYA) patients. The aim of this retrospective case series study was to evaluate the impact of the diagnostic biopsy method on staging, treatment, and treatment-related outcomes in pediatric/AYA patients with melanoma. Among 103 pediatric/AYA patients with atypical cutaneous melanocytic lesions, the most common biopsy method was partial shave (68/103, 66.0%) followed by punch (20/103, 19.4%), excisional (14/103, 13.6%), and incisional nonshave (1/103, 1%). Over half of all biopsies yielded a positive deep margin, reflecting compromised microstaging (56/103, 55.4%), the majority occurred following partial shave (52/56, 92.9%) compared with other techniques (P < 0.001). All 11 patients with wider surgical target margins of wide local excision and 8/9 patients with sentinel lymph node biopsy performed due to positive deep margin, underwent a partial shave biopsy (P = 0.05 and 0.32, respectively). Almost half of all patients who underwent partial shave biopsy had a clinically suspected abnormal melanocytic tumor prior to biopsy (31/68, 45.6%; P = 0.03). Of 56 patients who had compromised microstaging, 17 (30.4%) had a diagnosis of melanoma (P = 0.17). Pediatric/AYA patients frequently undergo partial shave biopsy, which is associated with more invasive definitive surgical treatment due to compromised microstaging. These results may help optimize care of patients with cutaneous melanocytic tumors.

Multi-dimensional immunotyping of human NF1-associated peripheral nerve sheath tumors uncovers tumor-associated macrophages as key drivers of immune evasion in the tumor microenvironment.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas and the leading cause of mortality in individuals with neurofibromatosis type 1 (NF1). Despite many clinical trials, outcomes for patients with MPNST have remained stagnant and most succumb to their disease; thus, novel therapeutic approaches are needed. A better understanding of the MPNST immune ecosystem will aid in the development of strategies to activate the immune system against the tumor. Herein, we profile the tumor immune microenvironment (TIME) in NF1-associated peripheral nerve sheath tumors (PNST) to discover insights on the role that tumor-infiltrating immune cells play in malignant transformation. EXPERIMENTAL DESIGN: Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with NF1-PNST, we dissected the TIME by using immunohistochemistry, multiparameter flow cytometry, and comparative transcriptomic studies. RESULTS: Immunophenotyping confirmed increased immune cells infiltration during malignant progression, with a predominance of infiltrating myeloid cells, particularly CD163+ tumor-associated macrophages (TAM). The T cells within MPNST exhibited signs of tumor activation, characterized by high PD-1 expression. Additionally, MPNST specimens demonstrated elevated levels of immunosuppressive TAM, with heightened PD-L1 expression. The proportion of CD163+ myeloid cells within the TIME correlated with poorer progression free survival. Notably, loss of H3K27 trimethylation correlated with low immune cell infiltration in MPNST. CONCLUSIONS: Malignant transformation of NF1-PNST is characterized by an immunosuppressive microenvironment comprising of TAM with high expression of PD-L1, which are associated with inferior outcomes. These findings suggest a clinical potential of immune modulating therapeutics that can unleash an anti-tumor immune response.

Rib-on-pelvis deformity: a modifiable driver of pain and poor health-related quality of life in cerebral palsy.

PURPOSE: Cerebral Palsy (CP) often presents with a sweeping thoracolumbar scoliosis and pelvic obliquity. With severe pelvic obliquity, the ribs come into contact with the high side of the oblique pelvis, termed rib-on-pelvis deformity (ROP). ROP can result in costo-iliac impingement, or pain associated with ROP, and can also adversely affect breathing and sitting balance. The goal of this study was to evaluate whether CP patients with ROP have worse health-related quality of life (HRQOL) before surgery and a greater improvement in HRQOL after surgery. METHODS: A retrospective analysis of a prospectively collected, multicenter, international registry was performed for all nonambulatory patients with CP treated with spinal fusion with at least two-year follow-up. HRQOL was measured via the Caregiver Priorities & Child Health Index of Life with Disabilities (CPCHILD) questionnaire domains (0 = most disability, 100 = least disability). ROP was defined as having a rib distal to the superior portion of the iliac crest on preop upright radiographs. The ROP group and control group without ROP were compared regarding six domain scores and total score of CPCHILD. Multiple linear regression was used to control for curve apex location, major coronal Cobb angle, type of tone, and pelvic obliquity. RESULTS: 340 patients met inclusion criteria (52% female, mean age 14.0 years). The mean major coronal Cobb angle was 81 degrees and mean pelvic obliquity was 22 degrees. 176 patients (51.8%) had ROP while 164 patients (48.2%) did not. ROP was independently associated with worse preoperative Positioning/Transfers/Mobility (PTM), Comfort & Emotions (C&E), and total CPCHILD score via the CPCHILD questionnaire (p < 0.05). Patients with preoperative ROP experienced a greater improvement in the C&E and PTM domains as well as total CPCHILD score than patients without ROP (p < 0.05). CONCLUSION: CP patients with rib-on-pelvis deformity experience more pain and worse HRQOL than patients without this deformity. These patients experienced a greater improvement in HRQOL after spinal fusion measured via the CPCHILD questionnaire.

Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.

Macrophage efferocytosis prevents apoptotic cell (AC) accumulation and triggers inflammation-resolution pathways. The mechanisms linking efferocytosis to resolution often involve changes in macrophage metabolism, but many gaps remain in our understanding of these processes. We now report that efferocytosis triggers an indoleamine 2,3-dioxygenase-1 (IDO1)-dependent tryptophan (Trp) metabolism pathway that promotes several key resolution processes, including the induction of pro-resolving proteins, such interleukin-10, and further enhancement of efferocytosis. The process begins with upregulation of Trp transport and metabolism, and it involves subsequent activation of the aryl hydrocarbon receptor (AhR) by the Trp metabolite kynurenine (Kyn). Through these mechanisms, macrophage IDO1 and AhR contribute to a proper resolution response in several different mouse models of efferocytosis-dependent tissue repair, notably during atherosclerosis regression induced by plasma low-density lipoprotein (LDL) lowering. These findings reveal an integrated metabolism programme in macrophages that links efferocytosis to resolution, with possible therapeutic implications for non-resolving chronic inflammatory diseases, notably atherosclerosis.

Twisting vortex lines regularize Navier-Stokes turbulence.

Fluid flows are intrinsically characterized via the topology and dynamics of underlying vortex lines. Turbulence in common fluids like water and air, mathematically described by the incompressible Navier-Stokes equations (INSE), engenders spontaneous self-stretching and twisting of vortex lines, generating a complex hierarchy of structures. While the INSE are routinely used to describe turbulence, their regularity remains unproven; the implicit assumption being that the self-stretching is ultimately regularized by viscosity, preventing any singularities. Here, we uncover an inviscid regularizing mechanism stemming from self-stretching itself, by analyzing the flow topology as perceived by an observer aligned with the vorticity vector undergoing amplification. While, initially, vorticity amplification occurs via increasing twisting of vortex lines, a regularizing anti-twist spontaneously emerges to prevent unbounded growth. By isolating a vortex, we additionally demonstrate the genericity of this self-regularizing anti-twist. Our work, directly linking dynamics of vortices to turbulence statistics, reveals how the Navier-Stokes dynamics avoids the development of singularities even without the aid of viscosity.

A tale of two constructs: combined assessment of demoralization and subjective incompetence.

Demoralization comprises multiple dimensions. Among them, Subjective Incompetence (SI) is the perception of being incapable of appropriate action in demanding circumstances. SI may be an early sign of demoralization preceding hopelessness, thus we aimed at integrating items related to Subjective Incompetence into the clinical assessment of demoralization. We assessed 414 subjects from the general population with the Demoralization Scale, 24 items (DS24) and the Subjective Incompetence Scale, 12 items (SIS12). We used multiple approaches to detect the optimal number of factors and their item structure, then conducted Bayesian Item Response Theory analyses to study item psychometric properties. Item Response Theory models were used to extrapolate latent severity ratings of clinical dimensions. We modelled the DS24 with five factors (Disheartenment, Sense of Failure, Helplessness, Irritability, Loss of Purpose) and the SIS12 with three (Subjective Incompetence, Inability to plan, Inability to Deal). The more complex IRT model had the best predictive value and helped to identify the items with better discrimination properties across the different dimensions. Twenty items were retained and used to develop the combined Demoralization and Subjective Incompetence Scale (DSIS20), which maintained high correlation with raw and latent trait scores of the longer versions. We combined selected items of the DS24 and the SIS12 to develop the DSIS20, a shorter assessment instrument that includes Subjective Incompetence as well as other clinical dimensions of demoralization. Further study may clarify if DSIS20 may be helpful for the early detection of demoralization.

Antiretroviral Therapy and Cardiovascular Risk in People With HIV in the United States-An Updated Analysis.

Background: Several antiretroviral therapy (ART) medications have been associated with increased cardiovascular risk, but less is known about the safety of modern ART. We sought to compare the risk of major adverse cardiac events (MACEs) among different ART regimens. Methods: Using insurance claims databases from 2008 to 2020, we identified adults aged <65 years who newly initiated ART. We compared non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens to protease inhibitors (PI)- and integrase inhibitors (INSTI)-based regimens. We used propensity score-weighted Kaplan-Meier functions to estimate the 6, 12, 18, 24, 36, and 48 months' risk and risk differences (RD) of MACE. Results: Among 37 935 ART initiators (median age, 40 years; 23% female; 26% Medicaid-insured), 45% started INSTI-, 16% PI-, and 39% NNRTI-based regimens. MACE occurred in 418 individuals (1.1%) within 48 months after ART initiation. Compared to NNRTI initiators, the risk of MACE was higher at 12 months (RD, 0.50; 95% CI, 0.14-0.99), 18 months (RD, 0.53; 95% CI, 0.11-1.06), and 24 months (RD, 0.62; 95% CI, 0.04-1.29) for PI initiators, and at 12 (RD, 0.20; 95% CI, 0.03-0.37) and 18 months (RD, 0.31; 95% CI, 0.06-0.54) for INSTI initiators; the precision of estimates was limited for longer duration of follow-up. Conclusions: Among ART initiators, PI-based and INSTI-based regimens were associated with higher short-term risk of MACE compared to NNRTI-based regimens. The pattern of association between INSTIs and PIs with excess risk of MACE was similar.

Patient-reported Outcomes After Medial Meniscus Root Tear Repair Versus Other Medial Meniscus Repairs: An Exploratory Meta-analysis of Single-arm Cohorts.

INTRODUCTION: This study aimed to (1) compare patient-reported outcome measures between patients who underwent medial meniscus root tear (MMRT) repair and those who underwent other types of medial meniscus repair, and (2) identify factors associated with observed differences. METHODS: A literature search identified studies reporting PROMs-knee injury and osteoarthritis outcome score (KOOS) or visual analog scale (VAS) for pain-after repair of the medial meniscus. Studies were excluded if outcomes were not separated by tear type or reported graphically, different or no outcomes reported, no repair or repair with a sutureless method, follow-up greater than 72 months, case report, and systematic review. Patient-reported outcome measures and demographics were summarized as sample-weighted means and compared using t-tests. Mixed model linear regressions were fit predicting postoperative PROMs adjusted for tear type, preoperative PROMs, and follow-up time. F statistics of type III tests of fixed effects were compared. RESULTS: Eighteen articles were included, n = 10 received MMRT repair and n = 8 other tear repairs. Postoperative values for all KOOS scores were less for the MMRT repair group compared with the other tear repair group, VAS pain was not statistically different. Tear type was a stronger predictor for postoperative PROMs than the preoperative score and duration of follow-up for all KOOS scores, but not VAS pain. On average, the MMRT repair group had shorter follow-up, more women, older age, and greater BMI. DISCUSSION: All postoperative PROMs except for VAS pain were worse for patients who underwent MMRT repair compared with patients who underwent other types of medial meniscus repair. Tear type was a better predictor of postoperative PROMs despite intergroup differences in preoperative PROMs and duration of follow-up. Relative risk factors for MMRT compared with other types of medial meniscus tears include older age, greater BMI, and female sex.

Acceptability and feasibility of trauma- and violence-informed care for intimate partner violence.

BACKGROUND/OBJECTIVES: Intimate partner violence (IPV) and child physical abuse frequently co-occur, yet IPV-exposed children are not routinely evaluated for abuse. Furthermore, IPV survivors often seek care for their children but not for themselves, making pediatric visits an opportunity to address IPV. We developed a trauma- and violence-informed care (TVIC)-based model that 1) evaluated IPV-exposed children and 2) linked survivor-caregivers to an IPV advocate. We aimed to assess the feasibility and acceptability of the model. PARTICIPANTS: Children < 3 who were reported to Child Protective Services (CPS) for exposure to IPV and their survivor-caregiver. METHODS: To examine feasibility, we calculated the percentage of 1) eligible children evaluated and 2) caregivers who met with an IPV advocate during the child's visit and followed up with the advocate. To assess acceptability, we conducted qualitative interviews with 30/41 caregivers about their perceptions of the model. RESULTS: From 7/1/20-6/30/22, 49 (22.7 %) of 216 eligible children were evaluated. Of 41 caregivers, six already were receiving IPV services; Of the remaining 35, 24 (68.6 %) met with an IPV advocate, and 22 (91.7 %) had ≥1 follow-up visit with an advocate. We identified three themes: 1) Motivations for the visit, 2) Engagement with the model, and 3) Benefits. Caregivers attended the visit due to behavioral concerns about the child and a desire to comply with CPS. Engagement occurred as medical providers established rapport and provided support without judgment. Benefits included recognizing the impact of IPV on the child and immediate linkage to advocacy services. CONCLUSION: A TVIC-based model is feasible and acceptable and could improve caregivers' engagement with the evaluation of IPV-exposed children for abuse and with IPV services, which have the potential to improve safety and promote well-being.

Chemical Bond Energies of Organic Peroxides: From CH3OOCH3 to High-Molecular-Weight Industrially Significant Compounds.

Peroxides are of some importance in a number of industrial areas, as well as in atmospheric and low-temperature combustion chemistries. Although there are some organic peroxides that are powerful explosives, such as hexamethylene triperoxide diamine, their principal use is as initiators in polymerization reactions in the plastics and rubber industries since the O-O bond is easily cleaved to generate two reactive free radicals. This gives rise to concern about safety issues in both the manufacture of and the deployment of these compounds since they are strong oxidizers. A measure of these safety concerns can be achieved by determining the chemical bond energy or bond dissociation energy (BDE) for the following process: R-O-O-R' → RO• + R'O• since those with very weak O-O bonds are most likely to be problematic. We have used the midlevel model chemistry G4 to compute the BDE of a number of organic peroxides ranging from the simplest dialkyl peroxide to diacyl, peroxy ester, and peroxycarbonate peroxides. In addition, we have used much higher levels of theory to benchmark the chemical bond energy of dimethyl peroxide in the expectation that this will anchor all future determinations.

Hospital Readmissions Among Infants With Neonatal Opioid Withdrawal Syndrome.

Importance: Although cases of neonatal opioid withdrawal syndrome (NOWS) increased 5-fold in recent years, no study has examined national hospital readmission rates for these infants. Objective: To examine hospital readmissions for infants with and without NOWS. Design, Setting, and Participants: This retrospective cohort study analyzed serial cross-sectional samples of US hospital discharge records from the Nationwide Readmissions Database for calendar years 2016 to 2020. Infants with NOWS were identified using International Classification of Diseases, Tenth Revision, Clinical Modification codes. The data analysis was performed between January 5, 2023, and May 6, 2024. Exposure: Neonatal opioid withdrawal syndrome. Main Outcome and Measures: Survey-weighted logistic regression was used to examine 90-day all-cause and cause-specific hospital readmissions. Multivariable models adjusted for sex, low birth weight, gestational age, multiple gestation, type of insurance, and year of birth. Results: Of the 13 855 246 newborns identified in this weighted analysis, 89 018 (0.6%) were diagnosed with NOWS, of whom 53.8% were male and 81.1% born full-term (>36 weeks gestation). The 90-day all-cause readmission rate was 4.2% for infants with NOWS compared with 3.0% for those without NOWS (P < .001). After risk adjustment, the odds of all-cause readmission were higher among infants with NOWS (adjusted odds ratio [AOR], 1.18; 95% CI, 1.08-1.29). Infants with NOWS had significantly higher odds of readmissions for seizures (AOR, 1.58; 95% CI, 1.01-2.46), failure to thrive (AOR, 1.99; 95% CI, 1.36-2.93), traumatic brain injury (AOR, 2.95; 95% CI, 1.76-4.93), and skull fractures (AOR 3.72; 95% CI, 2.33-5.93). Infants with NOWS had higher odds of receiving a diagnosis of confirmed maltreatment (AOR, 4.26; 95% CI, 2.19-8.27), including for neglect (AOR, 14.18; 95% CI, 5.55-36.22) and physical abuse (AOR, 2.42; 95% CI, 0.93-6.29); however, the latter finding was not statistically significant. Conclusions and Relevance: In this nationally representative cohort study, infants with NOWS were at increased risk of readmission for any cause as well as for trauma and confirmed maltreatment. These findings may in part reflect the dual stressors that mothers with opioid use disorder face in caring for a newborn with NOWS in the context of a substance use disorder and underscore the need for family-based, in-home services that focus concurrently on substance use treatment and parenting support.

Natural selection on floral volatiles and other traits can change with snowmelt timing and summer precipitation.

Climate change is disrupting floral traits that mediate mutualistic and antagonistic species interactions. Plastic responses of these traits to multiple shifting conditions may be adaptive, depending on natural selection in new environments. We manipulated snowmelt date over three seasons (3-11 d earlier) in factorial combination with growing-season precipitation (normal, halved, or doubled) to measure plastic responses of volatile emissions and other floral traits in Ipomopsis aggregata. We quantified how precipitation and early snowmelt affected selection on traits by seed predators and pollinators. Within years, floral emissions did not respond to precipitation treatments but shifted with snowmelt treatment depending on the year. Across 3 yr, emissions correlated with both precipitation and snowmelt date. These effects were driven by changes in soil moisture. Selection on several traits changed with earlier snowmelt or reduced precipitation, in some cases driven by predispersal seed predation. Floral trait plasticity was not generally adaptive. Floral volatile emissions shifted in the face of two effects of climate change, and the new environments modulated selection imposed by interacting species. The complexity of the responses underscores the need for more studies of how climate change will affect floral volatiles and other floral traits.

Timing of coronary artery bypass grafting after myocardial infarction influences late survival.

Objectives: The role of timing of coronary artery bypass grafting after acute myocardial infarction on early and late outcomes remains uncertain. Methods: We reviewed 1631 consecutive adult patients who underwent isolated coronary artery bypass grafting with information on timing of acute myocardial infarction. Early and late mortality were compared between patients receiving coronary artery bypass grafting within 24 hours after acute myocardial infarction, between 1 and 7 days after acute myocardial infarction, and more than 7 days after acute myocardial infarction. Sensitivity analyses were performed in subgroups of patients with ST-segment elevation myocardial infarction or non-ST-segment elevation myocardial infarction, and other high-risk groups. Results: A total of 124 patients (5.7%) underwent coronary artery bypass grafting within 24 hours, 972 patients (51.2%) received coronary artery bypass grafting between 1 and 7 days after acute myocardial infarction, and 535 patients (43.2%) underwent coronary artery bypass grafting more than 7 days after acute myocardial infarction. Overall operative mortality was 2.7% with comparable adjusted early mortality among 3 groups. Over a median follow-up of 13.5 years (interquartile range, 8.9-17.1), compared with patients receiving coronary artery bypass grafting between 1 and 7 days after acute myocardial infarction, those receiving coronary artery bypass grafting at 7 days had greater adjusted risk for late overall mortality (hazard ratio, 1.39, 95% CI, 1.16-1.67; P < .001), whereas those receiving coronary artery bypass grafting within 24 hours had comparable risk of late overall mortality (hazard ratio, 1.12, 95% CI, 0.86-1.47; P = .39). Timing of coronary artery bypass grafting was associated with late mortality in patients with non-ST-segment elevation myocardial infarction (patients receiving coronary artery bypass grafting at >7 days had a higher risk of late mortality [hazard ratio, 1.38, 95% CI, 1.14-1.67, P < .001] compared with those receiving coronary artery bypass grafting between 1 and 7 days), but not in patients with ST-segment elevation myocardial infarction. Conclusions: Early revascularization through coronary artery bypass grafting within 7 days during the same hospitalization appears beneficial, especially for patients presenting with non-ST-segment elevation myocardial infarction.

Randomized Phase III SIERRA Trial of 131I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care for Relapsed/Refractory AML.

PURPOSE: Older patients with relapsed or refractory AML (RR AML) have dismal prognoses without allogeneic hematopoietic cell transplantation (alloHCT). SIERRA compared a targeted pretransplant regimen involving the anti-CD45 radioconjugate 131I-apamistamab with conventional care. METHODS: SIERRA (ClinicalTrials.gov identifier: NCT02665065) was a phase III open-label trial. Patients age ≥55 years with active RR AML were randomly assigned 1:1 to either an 131I-apamistamab-led regimen before alloHCT or conventional care followed by alloHCT if initial complete remission (CR)/CR with incomplete platelet recovery (CRp) occurred. Initial response was assessed 28-56 days after alloHCT in the 131I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive 131I-apamistamab followed by alloHCT. The primary end point was durable complete remission (dCR) lasting 180 days after initial CR/CRp. Secondary end points were overall survival (OS) and event-free survival (EFS), assessed hierarchically in the intention-to-treat (ITT) population. RESULTS: The ITT population included 153 patients (131I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received 131I-apamistamab and alloHCT, with six patients (13.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with 131I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; P < .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; P = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR <1 favoring 131I-apamistamab. Grade ≥3 treatment-related adverse events occurred in 59.7% and 59.2% of the 131I-apamistamab and conventional care groups, respectively. CONCLUSION: The 131I-apamistamab-led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. 131I-apamistamab was well tolerated and could address an unmet need in this population.

The enigmatic Triassic ovulate reproductive structures of Dordrechtites are recurved cupules fundamentally comparable to the cupules of Doylea and similar plants.

Recent paleobotanical discoveries have renewed interest in the distinctively recurved, seed-bearing cupules of Mesozoic plants, which are important for understanding seed plant phylogeny and the origin of the second integument of the angiosperm ovule. Reanalysis of the enigmatic seed-bearing organ Dordrechtites elongatus from the Triassic of South Africa, the type species of the genus, combined with information from similar material from Antarctica, Argentina and Australia, indicates that Dordrechtites is a highly modified lateral branch of a seed cone. Short lateral projections from a primary cone axis each bear several Dordrechtites units. Each unit consists of a long stalk bearing a straight to sometimes recurved cupule with a long distal extension beyond the cupule apex. Each cupule is flattened in a plane perpendicular to the stalk and distal projection and contains up to two seeds. Structural similarities between Dordrechtites and the cupules of Doyleales indicate that they are homologous, providing new evidence for a close relationship. The persistent cupule stalk and apical extension of Dordrechtites, combined with the flattened cupule, suggests modification for wind and water dispersal.