The double-edged sword of potassium and sodium fertilization in xylem embolism resistance of two Eucalyptus species under drought stress.

Sodium (Na+) is a beneficial element for most plants and may replace potassium (K+) in osmoregulatory process to a certain extent, increasing plant water use efficiency. Thus, understanding coordinated mechanisms underlying the combined use of K+ and Na+ in tree drought tolerance is a key challenge for forestry in dealing with productivity and water limitations. A pot experiment with three ratios of K/Na (K-supplied, partial K replacement by Na, and K-deficient plants) and two water regimes, well-watered (W+) and water-stressed (W-), was conducted on saplings of two Eucalyptus species with contrasting drought sensitivities. We evaluated the point of stomatal closure (Pgs90), xylem water potential at 12, 50, and 88% embolized xylem area (P12, P50, P88), hydraulic safety margin, leaf gas exchange (A, E, gs, and dark respiration), pre-dawn and midday leaf water potential (ΨPD and ΨMD), long-term water use efficiency (WUEL) and total dry mass. Partial K replacement by Na increased leaf gas exchange, WUEL, and total dry mass, while Pgs90, P12, P50, P88, and ΨMD decreased (were more negative), compared with plants exclusively supplied with K and K-deficient plants of both species. Fertilized plants had narrower hydraulic safety margins than K-deficient plants, indicating that these Eucalyptus species adopt the functional adaptive strategy of operating close to their hydraulic limits to maximize carbon uptake while increasing the risk of hydraulic failure under drought stress.

Discovery and validation of plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance and diabetes progression or regression among Puerto Rican adults.

AIMS/HYPOTHESIS: Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites. METHODS: We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA1c) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors. RESULTS: Plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures. CONCLUSIONS/INTERPRETATION: The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes.

The potential impact of removing a ban on electronic nicotine delivery systems using the Mexico smoking and vaping model (SAVM).

Objective: To develop the Mexico Smoking and Vaping Model (Mexico SAVM) to estimate cigarette and electronic nicotine delivery systems (ENDS) prevalence and the public health impact of legalizing ENDS use. Methods: SAVM, a cohort-based discrete-time simulation model, compares two scenarios. The ENDS-Restricted Scenario estimates smoking prevalence and associated mortality outcomes under the current policy of an ENDS ban, using Mexico-specific population projections, death rates, life expectancy, and smoking and e-cigarette prevalence. The ENDS-Unrestricted Scenario projects smoking and vaping prevalence under a hypothetical scenario where ENDS use is allowed. The impact of legalizing ENDS use is estimated as the difference in smoking- and vaping-attributable deaths (SVADs) and life-years lost (LYLs) between the ENDS-Restricted and Unrestricted scenarios. Results: Compared to a national ENDS ban, The Mexico SAVM projects that legalizing ENDS use could decrease smoking prevalence by 40.1% in males and 30.9% in females by 2049 compared to continuing the national ENDS ban. This reduction in prevalence would save 2.9 (2.5 males and 0.4 females) million life-years and avert almost 106 (91.0 males and 15.5 females) thousand deaths between 2025 and 2049. Public health gains decline by 43% to 59,748 SVADs averted when the switching rate is reduced by half and by 24.3% (92,806 SVADs averted) with a 25% ENDS risk level from that of cigarettes but increased by 24.3% (121,375 SVADs averted) with the 5% ENDS risk. Conclusions: Mexico SAVM suggests that greater access to ENDS and a more permissive ENDS regulation, simultaneous with strong cigarette policies, would reduce smoking prevalence and decrease smoking-related mortality. The unanticipated effects of an ENDS ban merit closer scrutiny, with further consideration of how specific ENDS restrictions may maximize public health benefits.

In Vitro and In Vivo Efficacy of a Stroma-Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer.

More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV), whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer, uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404), a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.

Gnocchi Implants: An Unusual Differential Diagnosis for Breast Implant Rupture on Imaging.

Background: Although breast implant techniques have advanced considerably since the first recorded augmentation procedure in 1895, rupture remains a significant complication. Proper diagnosis is vital for patients' well-being but can sometimes prove challenging when there is no documentation of the initial procedure. Methods: This report describes a 58-year-old woman with a 30-year history of subglandular periareolar breast augmentation who was referred for bilateral implant rupture identified on computed tomography performed to monitor a breast nodule. Results: Despite classic imaging findings suggesting bilateral intracapsular implant rupture, breast implant revision surgery revealed a dense capsule containing 6 small silicone implants with no ruptures. Conclusions: This is a unique case where radiographic imaging was misleading due to an undocumented unusual breast augmentation procedure that used multiple small "gnocchi-like" silicone implants. To our knowledge, this technique has never been described until now and should be noted by the surgical and radiological community.

Myeloperoxidase as a biomarker for intestinal-brain axis dysfunction induced by malnutrition and Cryptosporidium infection in weanling mice.

Cryptosporidiosis is a waterborne protozoal infection that may cause life-threatening diarrhea in undernourished children living in unsanitary environments. The aim of this study is to identify new biomarkers that may be related to gut-brain axis dysfunction in children suffering from the malnutrition/infection vicious cycle, necessary for better intervention strategies. Myeloperoxidase (MPO) is a well-known neutrophil-related tissue factor released during enteropathy that could drive gut-derived brain inflammation. We utilized a model of environmental enteropathy in C57BL/6 weanling mice challenged by Cryptosporidium and undernutrition. Mice were fed a 2%-Protein Diet (dPD) for eight days and orally infected with 107-C. parvum oocysts. C. parvum oocyst shedding was assessed from fecal and ileal-extracted genomic DNA by qRT-PCR. Ileal histopathology scores were assessed for intestinal inflammation. Prefrontal cortex samples were snap-frozen for MPO ELISA assay and NF-kb immunostaining. Blood samples were drawn by cardiac puncture after anesthesia and sera were obtained for serum amyloid A (SAA) and MPO analysis. Brain samples were also obtained for Iba-1 prefrontal cortex immunostaining. C. parvum-infected mice showed sustained stool oocyst shedding for six days post-infection and increased fecal MPO and inflammation scores. dPD and cryptosporidiosis led to impaired growth and weight gain. C. parvum-infected dPD mice showed increased serum MPO and serum amyloid A (SAA) levels, markers of systemic inflammation. dPD-infected mice showed greater MPO, NF-kB expression, and Iba-1 immunolabeling in the prefrontal cortex, an important brain region involved in executive function. Our findings suggest MPO as a potential biomarker for intestinal-brain axis dysfunction due to environmental enteropathy.

Left Bundle Branch Area Pacing Versus Biventricular Pacing as Initial Strategy for Cardiac Resynchronization.

BACKGROUND: Left bundle branch area pacing (LBBAP) for cardiac resynchronization therapy (CRT) is an alternative to biventricular pacing (BiVp). OBJECTIVES: The purpose of this study was to compare the outcomes between LBBAP and BiVp as an initial implant strategy for CRT. METHODS: In this prospective multicenter, observational, nonrandomized study, first-time CRT implant recipients with LBBAP or BiVp were included. The primary efficacy outcome was a composite of heart failure (HF)-related hospitalization and all-cause mortality. The primary safety outcomes were acute and long-term complications. Secondary outcomes included postprocedural New York Heart Association functional class and electrocardiographic and echocardiographic parameters. RESULTS: A total of 371 patients (median follow-up of 340 days [IQR: 206-477 days]) were included. The primary efficacy outcome occurred in 24.2% in the LBBAP vs 42.4% in the BiVp (HR: 0.621 [95% CI: 0.415-0.93]; P = 0.021) group, driven by a reduction in HF-related hospitalizations (22.6% vs 39.5%; HR: 0.607 [95% CI: 0.397-0.927]; P = 0.021) without significant difference in all-cause mortality (5.5% vs 11.9%; P = 0.19) or differences in long-term complications (LBBAP: 9.4% vs BiVp: 15.2%; P = 0.146). LBBAP resulted in shorter procedural (95 minutes [IQR: 65-120 minutes] vs 129 minutes [IQR: 103-162 minutes]; P < 0.001) and fluoroscopy times (12 minutes [IQR: 7.4-21.1 minutes] vs 21.7 minutes [IQR: 14.3-30 minutes]; P < 0.001), shorter QRS duration (123.7 ± 18 milliseconds vs 149.3 ± 29.1 milliseconds; P < 0.001), and higher postprocedural left ventricular ejection fraction (34.1% ± 12.5% vs 31.4% ± 10.8%; P = 0.041). CONCLUSIONS: LBBAP as an initial CRT strategy resulted in a lower risk of HF-related hospitalizations compared to BiVp. A reduction in procedural and fluoroscopy times, shorter paced QRS duration, and improvements in left ventricular ejection fraction compared with BiVp were observed.

CD38 as a pan-hematologic target for chimeric antigen receptor T cells.

Many hematologic malignancies are not curable with chemotherapy and require novel therapeutic approaches. Chimeric antigen receptor (CAR) T-cell therapy is 1 such approach that involves the transfer of T cells engineered to express CARs for a specific cell-surface antigen. CD38 is a validated tumor antigen in multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL) and is also overexpressed in acute myeloid leukemia (AML). Here, we developed human CD38-redirected T cells (CART-38) as a unified approach to treat 3 different hematologic malignancies that occur across the pediatric-to-adult age spectrum. Importantly, CD38 expression on activated T cells did not impair CART-38 cells expansion or in vitro function. In xenografted mice, CART-38 mediated the rejection of AML, T-ALL, and MM cell lines and primary samples and prolonged survival. In a xenograft model of normal human hematopoiesis, CART-38 resulted in the expected reduction of hematopoietic progenitors, which warrants caution and careful monitoring of this potential toxicity when translating this new immunotherapy into the clinic. Deploying CART-38 against multiple CD38-expressing malignancies is significant because it expands the potential for this novel therapy to affect diverse patient populations.

Bronchial epithelial cell transcriptional responses to inhaled corticosteroids dictate severe asthmatic outcomes.

BACKGROUND: Inhaled corticosteroids (CSs) are the backbone of asthma treatment, improving quality of life, exacerbation rates, and mortality. Although effective for most, a subset of patients with asthma experience CS-resistant disease despite receiving high-dose medication. OBJECTIVE: We sought to investigate the transcriptomic response of bronchial epithelial cells (BECs) to inhaled CSs. METHODS: Independent component analysis was performed on datasets, detailing the transcriptional response of BECs to CS treatment. The expression of these CS-response components was examined in 2 patient cohorts and investigated in relation to clinical parameters. Supervised learning was used to predict BEC CS responses using peripheral blood gene expression. RESULTS: We identified a signature of CS response that was closely correlated with CS use in patients with asthma. Participants could be separated on the basis of CS-response genes into groups with high and low signature expression. Patients with low expression of CS-response genes, particularly those with a severe asthma diagnosis, showed worse lung function and quality of life. These individuals demonstrated enrichment for T-lymphocyte infiltration in endobronchial brushings. Supervised machine learning identified a 7-gene signature from peripheral blood that reliably identified patients with poor CS-response expression in BECs. CONCLUSIONS: Loss of CS transcriptional responses within bronchial epithelium was related to impaired lung function and poor quality of life, particularly in patients with severe asthma. These individuals were identified using minimally invasive blood sampling, suggesting these findings may enable earlier triage to alternative treatments.

Patterns of Birth Cohort‒Specific Smoking Histories in Brazil.

INTRODUCTION: Smoking prevalence has decreased considerably in Brazil from 34.8% in 1989 to 12.6% in 2019 owing to the implementation of strong tobacco control policies. However, recent data show that the downward trend may be stagnating. Detailed analyses of historical smoking patterns by birth cohort could guide tobacco control decision making in Brazil. METHODS: Using the 2008 Global Adult Tobacco Survey and the 2013 and 2019 National Health Surveys, historical smoking patterns in Brazil were estimated, supplemented with data from the 2006‒2019 Surveillance System of Risk Factors for Chronic Diseases by Telephone Interviews. Age‒period‒cohort models with constrained natural splines were applied to estimate the annual probabilities of smoking initiation and cessation, current smoker prevalence, and mean cigarettes smoked per day by age, gender, and birth cohort. Analysis was conducted in 2021‒2022. RESULTS: Current smoker prevalence has declined considerably since the 1950 and 1955 birth cohorts for males and females, respectively, reflecting decreased smoking initiation and increased smoking-cessation probabilities over time. Among female cohorts born on or after 2000, smoking initiation may be increasing even as their smoking cessation has increased considerably. Mean cigarettes smoked per day has remained relatively constant across period and cohorts, showing only a minor decrease among males. CONCLUSIONS: These detailed cohort-specific smoking parameters can be used to inform models that evaluate the impact of tobacco use and policies on long-term health outcomes and guide public health decision making in Brazil. Stagnant mean cigarettes smoked per day, increasing female smoking initiation, and limited improvement in male cessation among recent cohorts present challenges to tobacco control.

Assisted reality device to guide cardiac implantable device programming in distant rural areas.

BACKGROUND: Patients with cardiac implantable electronic devices (CIEDs) living in rural areas have difficulty obtaining follow-up visits for device interrogation and programming in specialized healthcare facilities. OBJECTIVE: To describe the use of an assisted reality device designed to provide front-line workers with real-time online support from a remotely located specialist (Realwear HTM-1; Realwear) during CIED assistance in distant rural areas. METHODS: This is a prospective study of patients requiring CIED interrogation using the Realwear HMT-1 in a remote rural population in Colombia between April 2021 and June 2022. CIED interrogation and device programming were performed by a general practitioner and guided by a cardiac electrophysiologist. Non-CIED-related medical interventions were allowed and analyzed. The primary objective was to determine the incidence of clinically significant CIED alerts. Secondary objectives were the changes medical interventions used to treat the events found in the device interrogations regarding non-CIED related conditions. RESULTS: A total of 205 CIED interrogations were performed on 139 patients (age 69 ± 14 years; 54% female). Clinically significant CIED alerts were reported in 42% of CIED interrogations, consisting of the detection of significant arrhythmias (35%), lead malfunction (3%), and device in elective replacement interval (3.9%). Oral anticoagulation was initiated in 8% of patients and general medical/cardiac interventions unrelated to the CIED were performed in 52% of CIED encounters. CONCLUSION: Remote assistance using a commercially available assisted reality device has the potential to provide specialized healthcare to patients in difficult-to-reach areas, overcoming current difficulties associated with RM, including the inability to change device programming. Additionally, these interactions provided care beyond CIED-related interventions, thus delivering significant social and clinical impact to remote rural populations.

SPCIS: Standardized Plant Community with Introduced Status database.

The movement of plant species across the globe exposes native communities to new species introductions. While introductions are pervasive, two aspects of variability underlie patterns and processes of biological invasions at macroecological scales. First, only a portion of introduced species become invaders capable of substantially impacting ecosystems. Second, species that do become invasive at one location may not be invasive in others; impacts depend on invader abundance and recipient species and conditions. Accounting for these phenomena is essential to accurately understand the patterns of plant invasion and explain the idiosyncratic results reflected in the literature on biological invasions. The lack of community-level richness and the abundance of data spanning broad scales and environmental conditions have until now hindered our understanding of invasions at a macroecological scale. To address this limitation, we leveraged quantitative surveys of plant communities in the USA and integrated and harmonized nine datasets into the Standardized Plant Community with Introduced Status (SPCIS) database. The database contains 14,056 unique taxa identified within 83,391 sampling units, of which 52.6% have at least one introduced species. The SPCIS database includes comparable information on plant species occurrence, abundance, and native status across the 50 U.S. States and Puerto Rico. SPCIS can be used to answer macro-scale questions about native plant communities and interactions with invasive plants. There are no copyright restrictions on the data, and we ask the users of this dataset to cite this paper, the respective paper(s) corresponding to the dataset sampling design (all references are provided in Data S1: Metadata S1: Class II-B-2), and the references described in Data S1: Metadata S1: Class III-B-4 as applicable to the dataset being utilized.

Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy.

Children living in poverty experience excessive relapse and death from newly diagnosed acute lymphoblastic leukemia (ALL). The influence of household poverty and neighborhood social determinants on outcomes from chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (r/r) leukemia is poorly described. We identified patients with r/r CD19+ ALL/lymphoblastic lymphoma treated on CD19-directed CAR T-cell clinical trials or with commercial tisagenlecleucel from 2012 to 2020. Socioeconomic status (SES) was proxied at the household level, with poverty exposure defined as Medicaid-only insurance. Low-neighborhood opportunity was defined by the Childhood Opportunity Index. Among 206 patients aged 1 to 29, 35.9% were exposed to household poverty, and 24.9% had low-neighborhood opportunity. Patients unexposed to household poverty or low-opportunity neighborhoods were more likely to receive CAR T-cell therapy with a high disease burden (>25%), a disease characteristic associated with inferior outcomes, as compared with less advantaged patients (38% vs 30%; 37% vs 26%). Complete remission (CR) rate was 93%, with no significant differences by household poverty (P = .334) or neighborhood opportunity (P = .504). In multivariate analysis, patients from low-opportunity neighborhoods experienced an increased hazard of relapse as compared with others (P = .006; adjusted hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.3-4.1). There was no difference in hazard of death (P = .545; adjusted HR, 1.2; 95% CI, 0.6-2.4). Among children who successfully receive CAR T-cell therapy, CR and overall survival are equitable regardless of proxied SES and neighborhood opportunity. Children from more advantaged households and neighborhoods receive CAR T-cell therapy with a higher disease burden. Investigation of multicenter outcomes and access disparities outside of clinical trial settings is warranted.

Opportunistic Infections in Patients with Inflammatory Bowel Disease Treated with Advanced Therapies: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Advanced therapies for inflammatory bowel disease [IBD] could potentially lead to a state of immunosuppression with an increased risk of opportunistic infections [OIs]. We aimed to provide an update on the incidence of OIs among adult IBD patients in randomized controlled trials [RCTs] of approved biologics and small-molecule drugs [SMDs]. Also, we aimed to describe OI definitions utilized in RCTs, to ultimately propose a standardized definition. METHODS: Electronic databases were searched from January 1, 1990, until April 16, 2022. Our primary outcome was incidence rate of overall OIs among IBD patients exposed and unexposed to biologics or SMDs. We also describe specific OIs reported in included trials, as well as definitions of OIs within studies when provided. RESULTS: Ninety studies were included. The incidence rates of reported OIs were 0.42 and 0.21 per 100 person-years in patients exposed to advanced therapies and placebo, respectively. This was highest for anti-tumour necrosis factors [0.83 per 100 person-years] and Janus kinase inhibitors [0.55 per 100 person-years] and lowest for anti-integrins and ozanimod. On meta-analysis, no increased risk of OIs was observed. None of the studies provided a detailed definition of OIs, or a comprehensive list of infections considered as OIs. CONCLUSION: Different mechanisms of action may have specific OI profiles. In the absence of a uniform definition of OIs, these estimates are less reliable. We propose a definition to be used in future studies to help provide standardized reporting. When using this definition, we saw significant differences in incidence rates of OIs across mechanisms of action.

Myeloperoxidase as a biomarker for intestinal-brain axis dysfunction induced by malnutrition and Cryptosporidium infection in weanling mice

Abstract Cryptosporidiosis is a waterborne protozoal infection that may cause life-threatening diarrhea in undernourished children living in unsanitary environments. The aim of this study is to identify new biomarkers that may be related to gut-brain axis dysfunction in children suffering from the malnutrition/infection vicious cycle is necessary for better intervention strategies. Myeloperoxidase (MPO) is a well-known neutrophil-related tissue factor released during enteropathy that could drive gut-derived brain inflammation. We utilized a model of environmental enteropathy in C57BL/6 weanling mice challenged by Cryptosporidium and undernutrition. Mice were fed a 2%-Protein Diet (dPD) for eight days and orally infected with 107-C. parvum oocysts. C. parvum oocyst shedding was assessed from fecal and ileal-extracted genomic DNA by qRT-PCR. Ileal histopathology scores were assessed for intestinal inflammation. Prefrontal cortex samples were snap-frozen for MPO ELISA assay and NF-kb immunostaining. Blood samples were drawn by cardiac puncture after anesthesia and sera were obtained for serum amyloid A (SAA) and MPO analysis. Brain samples were also obtained for Iba-1 prefrontal cortex immunostaining. C. parvum-infected mice showed sustained stool oocyst shedding for six days post-infection and increased fecal MPO and inflammation scores. dPD and cryptosporidiosis led to impaired growth and weight gain. C. parvum-infected dPD mice showed increased serum MPO and serum amyloid A (SAA) levels, markers of systemic inflammation. dPD-infected mice showed greater MPO, NF-kB expression, and Iba-1 immunolabeling in the prefrontal cortex, an important brain region involved in executive function. Our findings suggest MPO as a potential biomarker for intestinal-brain axis dysfunction due to environmental enteropathy.

Total Ankle Replacement Versus Arthrodesis for End-Stage Ankle Osteoarthritis: A Randomized Controlled Trial.

BACKGROUND: End-stage ankle osteoarthritis causes severe pain and disability. There are no randomized trials comparing the 2 main surgical treatments: total ankle replacement (TAR) and ankle fusion (AF). OBJECTIVE: To determine which treatment is superior in terms of clinical scores and adverse events. DESIGN: A multicenter, parallel-group, open-label randomized trial. (ISRCTN registry number: 60672307). SETTING: 17 National Health Service trusts across the United Kingdom. PATIENTS: Patients with end-stage ankle osteoarthritis, aged 50 to 85 years, and suitable for either procedure. INTERVENTION: Patients were randomly assigned to TAR or AF surgical treatment. MEASUREMENTS: The primary outcome was change in Manchester-Oxford Foot Questionnaire walking/standing (MOXFQ-W/S) domain scores between baseline and 52 weeks after surgery. No blinding was possible. RESULTS: Between 6 March 2015 and 10 January 2019, a total of 303 patients were randomly assigned; mean age was 68 years, and 71% were men. Twenty-one patients withdrew before surgery, and 281 clinical scores were analyzed. At 52 weeks, the mean MOXFQ-W/S scores improved for both groups. The adjusted difference in the change in MOXFQ-W/S scores from baseline was -5.6 (95% CI, -12.5 to 1.4), showing that TAR improved more than AF, but the difference was not considered clinically or statistically significant. The number of adverse events was similar between groups (109 vs. 104), but there were more wound healing issues in the TAR group and more thromboembolic events and nonunion in the AF group. The symptomatic nonunion rate for AF was 7%. A post hoc analysis suggested superiority of fixed-bearing TAR over AF (-11.1 [CI, -19.3 to -2.9]). LIMITATION: Only 52-week data; pragmatic design creates heterogeneity of implants and surgical techniques. CONCLUSION: Both TAR and AF improve MOXFQ-W/S and had similar clinical scores and number of harms. Total ankle replacement had greater wound healing complications and nerve injuries, whereas AF had greater thromboembolism and nonunion, with a symptomatic nonunion rate of 7%. PRIMARY FUNDING SOURCE: National Institute for Health and Care Research Heath Technology Assessment Programme.

A new genus and species of Apseudidae, and a new species of Bunakenia (Crustacea: Tanaidacea: Apseudomorpha) from the Northwest Atlantic and Gulf of Mexico.

Examination of material from the Campeche region of the southern Gulf of Mexico revealed the presence of a new genus and species of Apseudidae that appears to be transitional between Bunakenia Guu and Apseudes Leach sensu lato. This new taxon, Pseudobunakenia anablesis n. gen., n. sp. is found throughout the Gulf of Mexico (GOM) and Northwest Atlantic as far north as South Carolina. It is known in the literature under the designation Apseudes spinosa Sars sensu Dawson and Apseudes sp. A (Heard et al.). Also, Bunakenia hamata n. sp. is described from offshore Georgia and is distributed from the Florida Gulf Coast and the Northwest Atlantic as far north as South Carolina. It is known in the literature under the designation Bunakenia sp. A (Heard et al.) and is the only known species of that genus in the GOM/NW Atlantic. It can be distinguished from its congeners by a combination of characters such as the pereonites having posterolateral apophyses, the antennule first peduncle article denticulate, the antennule accessory flagellum having five articles, and the first pereopod having four ventral propodal spiniform setae. A key to the known species is presented.

Life before impact in the Chicxulub area: unique marine ichnological signatures preserved in crater suevite.

To fully assess the resilience and recovery of life in response to the Cretaceous-Paleogene (K-Pg) boundary mass extinction ~ 66 million years ago, it is paramount to understand biodiversity prior to the Chicxulub impact event. The peak ring of the Chicxulub impact structure offshore the Yucatán Peninsula (México) was recently drilled and extracted a ~ 100 m thick impact-generated, melt-bearing, polymict breccia (crater suevite), which preserved carbonate clasts with common biogenic structures. We pieced this information to reproduce for the first time the macrobenthic tracemaker community and marine paleoenvironment prior to a large impact event at the crater area by combining paleoichnology with micropaleontology. A variable macrobenthic tracemaker community was present prior to the impact (Cenomanian-Maastrichtian), which included soft bodied organisms such as annelids, crustaceans and bivalves, mainly colonizing softgrounds in marine oxygenated, nutrient rich, conditions. Trace fossil assemblage from these upper Cretaceous core lithologies, with dominant Planolites and frequent Chondrites, corresponds well with that in the overlying post-impact Paleogene sediments. This reveals that the K-Pg impact event had no significant effects (i.e., extinction) on the composition of the macroinvertebrate tracemaker community in the Chicxulub region.

Cytosine base editing enables quadruple-edited allogeneic CART cells for T-ALL.

Allogeneic chimeric antigen receptor T-cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CARTs have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells, with between 90% and 99% efficiency to silence gene expression without creating DSBs, greatly reducing or eliminating undesired editing outcomes following multiplexed editing as compared with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). Using CBE, we developed 7CAR8, a CD7-directed allogeneic CART created using 4 simultaneous base edits. We show that CBE, unlike CRISPR-Cas9, does not impact T-cell proliferation, lead to aberrant DNA damage response pathway activation, or result in karyotypic abnormalities following multiplexed editing. We demonstrate 7CAR8 to be highly efficacious against T-cell acute lymphoblastic leukemia (T-ALL) using multiple in vitro and in vivo models. Thus, CBE is a promising technology for applications requiring multiplexed gene editing and can be used to manufacture quadruple-edited 7CAR8 cells, with high potential for clinical translation for relapsed and refractory T-ALL.