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The immunosuppressive tumor microenvironment (TME) is a formidable barrier to the success of adoptive cell therapies for solid tumors. Oncolytic immunotherapy with engineered adenoviruses (OAd) may disrupt the TME by infecting tumor cells, as well as surrounding stroma, to improve the functionality of tumor-directed chimeric antigen receptor (CAR)-T cells, yet efficient delivery of OAds to solid tumors has been challenging. Here we describe how mesenchymal stromal cells (MSCs) can be used to systemically deliver a binary vector containing an OAd together with a helper-dependent Ad (HDAd; combinatorial Ad vector [CAd]) that expresses interleukin-12 (IL-12) and checkpoint PD-L1 (programmed death-ligand 1) blocker. CAd-infected MSCs deliver and produce functional virus to infect and lyse lung tumor cells while stimulating CAR-T cell anti-tumor activity by release of IL-12 and PD-L1 blocker. The combination of this approach with administration of HER.2-specific CAR-T cells eliminates 3D tumor spheroids in vitro and suppresses tumor growth in two orthotopic lung cancer models in vivo. Treatment with CAd MSCs increases the overall numbers of human T cells in vivo compared to CAR-T cell only treatment and enhances their polyfunctional cytokine secretion. These studies combine the predictable targeting of CAR-T cells with the advantages of cancer cell lysis and TME disruption by systemic MSC delivery of oncolytic virotherapy: incorporation of immunostimulation by cytokine and checkpoint inhibitor production through the HDAd further enhances anti-tumor activity.

Purpose To critically review the literature reporting biomechanical outcomes of superior capsular reconstruction (SCR) for the treatment of massive and/or irreparable rotator cuff tears. Methods A systematic review was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines using the PubMed, MEDLINE, and Cochrane Library databases in August 2020. Cadaveric studies were assessed for glenohumeral translation, subacromial contact pressure, and superior humeral translation comparing SCR with an intact cuff with reference to a torn control state. Results A total of 15 studies (142 shoulders) were included in our data analysis. SCR showed improvements in superior humeral translation, subacromial contact force, and glenohumeral contact force when biomechanically compared with the massive and/or irreparably torn rotator cuff. No statistically significant differences were found between SCR and the intact rotator cuff regarding superior humeral translation (standard mean difference [SMD], 2.09 mm vs 2.50 mm; P = .54) or subacromial contact force (SMD, 2.85 mPa vs 2.83 mPa; P = .99). Significant differences were observed between SCR and the intact cuff for glenohumeral contact force only, in favor of the intact cuff (SMD, 1.73 N vs 5.45 N; P = .03). Conclusions SCR may largely restore static restraints to superior humeral translation in irreparable rotator cuff tears, although active glenohumeral compression is diminished relative to the intact rotator cuff. Clinical Relevance Investigating the biomechanical outcomes of SCR will help surgeons better understand the effectiveness of this treatment option.

BACKGROUND Same-day bilateral total knee arthroplasty (BiTKA) is a controversial topic in orthopedics, prompting a consensus statement to be released by national experts. To date, no studies have evaluated the trends of this method since these recommendations. This study utilized a national database to evaluate: 1) incidence; 2) patient characteristics; 3) hospital characteristics; and 4) inpatient course for same-day BiTKAs in the United States from 2009 to 2016. METHOD The National Inpatient Sample database was queried for individuals undergoing same-day BiTKAs, yielding 245,138 patients. Patient demographics included age, sex, race, obesity status and Charlson Comorbidity Index (CCI) score. Hospital characteristics consisted of location/teaching status, geographic region, charges, and costs. Inpatient course included length of stay, discharge disposition, and complications. RESULTS Same-day BiTKA incidence decreased from 5.6% to 4.0% over the study (p

The Iron and Classical Ages in the Near East were marked by population expansions carrying cultural transformations that shaped human history, but the genetic impact of these events on the people who lived through them is little-known. Here, we sequenced the whole genomes of 19 individuals who each lived during one of four time periods between 800 BCE and 200 CE in Beirut on the Eastern Mediterranean coast at the center of the ancient world's great civilizations. We combined these data with published data to traverse eight archaeological periods and observed any genetic changes as they arose. During the Iron Age (∼1000 BCE), people with Anatolian and South-East European ancestry admixed with people in the Near East. The region was then conquered by the Persians (539 BCE), who facilitated movement exemplified in Beirut by an ancient family with Egyptian-Lebanese admixed members. But the genetic impact at a population level does not appear until the time of Alexander the Great (beginning 330 BCE), when a fusion of Asian and Near Easterner ancestry can be seen, paralleling the cultural fusion that appears in the archaeological records from this period. The Romans then conquered the region (31 BCE) but had little genetic impact over their 600 years of rule. Finally, during the Ottoman rule (beginning 1516 CE), Caucasus-related ancestry penetrated the Near East. Thus, in the past 4,000 years, three limited admixture events detectably impacted the population, complementing the historical records of this culturally complex region dominated by the elite with genetic insights from the general population.

Conventional 3D printing approaches are restricted to building up material in a layer-by-layer format, which is more appropriately considered “2.5-D” printing. The layered structure inherently results in significant mechanical anisotropy in printed parts, causing the tensile strength in the build direction (z-axis) to be only a fraction of the in-plane strength – a decrease of 50–75% is common. In this study, a novel “z-pinning” approach is described that allows continuous material to be deposited across multiple layers within the volume of the part. The z-pinning process is demonstrated using a Fused Filament Fabrication (FFF) printer for polylactic acid (PLA) and carbon fiber reinforced PLA. For both materials, z-pinning increased the tensile strength and toughness in the z-direction by more than a factor of 3.5. Direct comparisons to tensile strength in the x-axis showed a significant decrease in mechanical anisotropy as the volume of the pin was increased relative to the void in the rectilinear grid structure. In fact, the PLA sample with the largest pin volume demonstrated mechanically isotropic properties within the statistical uncertainty of the tests. Tensile test results were also analyzed relative to the functional area resisting deformation for each sample.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

Essentials Activated clotting factor X (FXa) acquires fibrinolytic cofactor function after cleavage by plasmin. FXa-mediated plasma fibrinolysis is enabled by active site modification blocking a second cleavage. FXa-directed oral anticoagulants (DOACs) alter FXa cleavage by plasmin. DOACs enhance FX-dependent fibrinolysis and plasmin generation by tissue plasminogen activator. Background When bound to an anionic phospholipid-containing membrane, activated clotting factor X (FXa) is sequentially cleaved by plasmin from the intact form, FXaα, to FXaβ and then to Xa33/13. Tissue-type plasminogen activator (t-PA) produces plasmin and is the initiator of fibrinolysis. Both FXaβ and Xa33/13 enhance t-PA-mediated plasminogen activation. Although stable in experiments using purified proteins, Xa33/13 rapidly loses t-PA cofactor function in plasma. Bypassing this inhibition, covalent modification of the FXaα active site prevents Xa33/13 formation by plasmin, and the persistent FXaβ enhances plasma fibrinolysis. As the direct oral anticoagulants (DOACs) rivaroxaban and apixaban bind to the FXa active site, we hypothesized that they similarly modulate FXa fibrinolytic function. Methods DOAC effects on fibrinolysis and the t-PA cofactor function of FXa were studied in patient plasma, normal pooled plasma and purified protein experiments by the use of light scattering, chromogenic assays, and immunoblots. Results The plasma of patients taking rivaroxaban showed enhanced fibrinolysis correlating with FXaβ. In normal pooled plasma, the addition of rivaroxaban or apixaban also shortened fibrinolysis times. This was related to the cleavage product, FXaβ, which increased plasmin production by t-PA. It was confirmed that these results were not caused by DOACs affecting activated FXIII-mediated fibrin crosslinking, clot ultrastructure and thrombin-activatable fibrinolysis inhibitor activation in plasma. Conclusion The current study suggests a previously unknown effect of DOACs on FXa in addition to their well-documented anticoagulant role. By enabling the t-PA cofactor function of FXaβ in plasma, DOACs also enhance fibrinolysis. This effect may broaden their therapeutic indications.

A nondestructive neutron scattering method to precisely measure the hydrogen content in high-temperature steam-oxidized Zircaloy-4 cladding was developed. Zircaloy-4 cladding was used to produce hydrided specimens with hydrogen content up to ≈500 wppm. Following hydrogen charging, the hydrogen content of the hydrided specimens was measured using the vacuum hot extraction method, by which the samples with desired hydrogen concentrations were selected for the neutron study. The hydrided samples were then oxidized in steam up to ≈6.0 wt. % at 1100 °C. Optical microscopy shows that our hydriding procedure results in uniform distribution of circumferential hydrides across the wall thickness, and uniform oxide layers were formed on the sample surfaces by the steam oxidation. Small- and wide-angle neutron scattering were simultaneously performed to provide a quick (less than an hour per sample) measurement of the hydrogen content in various types of hydrided and oxidized Zircaloy-4. Our study demonstrates that the hydrogen in pre-oxidized Zircaloy-4 cladding can be measured very accurately by both small- and wide-angle neutron scattering. For steam-oxidized samples, the small-angle neutron scattering is contaminated with coherent scattering from additional structural features induced by the steam oxidation. However, the scattering intensity of the wide-angle neutron scattering increases proportionally with the hydrogen charged in the samples. The hydrogen content and wide-angle neutron scattering intensity are highly linearly correlated for the oxidized cladding samples examined in this work, and can be used to precisely determine the hydrogen content in steam-oxidized Zircaloy-4 samples. Hydrogen contents determined by neutron scattering of oxidation samples were also found to be consistent with the results of chemical analysis within acceptable margins for error.

Activation of 5-HT7 receptors influences memory as well as circadian rhythms and other processes. This study investigated the regulation of the 5-HT7 receptors in the hippocampus, a likely substrate for the effects of 5-HT7 receptor compounds on memory. Because endogenous serotonin release is higher during the active phase, and chronic treatment with a serotonin-selective reuptake inhibitor down-regulates 5-HT7 receptors, we hypothesized that 5-HT7 receptors exhibit 24-h variations. We also hypothesized that aging decreases 5-HT7 receptors in the hippocampus, as it does in the dorsal raphe nucleus, a brain site for serotonergic resetting of circadian rhythms. Male hamsters (young, 3-5 mos; old, 17-21 mos) exposed to a light:dark cycle were euthanized at 4 times of day (zeitgeber times [ZT]1, 6, 13, & 19; ZT12=time of lights:off). 5-HT7 receptor autoradiography was conducted on hippocampal sections using [3H]8-OH-DPAT [2nM] as the radioligand and SB-269970 [1μM] to define nonspecific binding. Slide-mounted sections and radioactive standards were apposed to X-ray films; the resultant autoradiograms were assessed by computer-assisted microdensitometry. Specific 5-HT7 receptor binding was robustly expressed in the dentate gyrus (DG) and CA1 but not in the CA2 or CA3. In the CA1 and DG, specific 5-HT7 receptor binding exhibited 24-h rhythms with troughs at night (P

Summary The Middle East region is important to understand human evolution and migrations but is underrepresented in genomic studies. Here, we generated 137 high-coverage physically phased genome sequences from eight Middle Eastern populations using linked-read sequencing. We found no genetic traces of early expansions out-of-Africa in present-day populations but found Arabians have elevated Basal Eurasian ancestry that dilutes their Neanderthal ancestry. Population sizes within the region started diverging 15–20 kya, when Levantines expanded while Arabians maintained smaller populations that derived ancestry from local hunter-gatherers. Arabians suffered a population bottleneck around the aridification of Arabia 6 kya, while Levantines had a distinct bottleneck overlapping the 4.2 kya aridification event. We found an association between movement and admixture of populations in the region and the spread of Semitic languages. Finally, we identify variants that show evidence of selection, including polygenic selection. Our results provide detailed insights into the genomic and selective histories of the Middle East., Graphical abstract, Highlights • Middle Easterners do not have ancestry from an early out-of-Africa expansion • Basal Eurasian and African ancestry in Arabians deplete their Neanderthal ancestry • Populations experienced bottlenecks overlapping aridification events • Identification of recent single and polygenic signals of selection in Arabia, A high-coverage resource of physically phased genomes from eight Middle Eastern populations generated via linked-read sequencing provides insights into a genetically understudied region and enables more comprehensive study of population history and the detection of millions of variants common to the Middle East but outside short-read accessibility masks and not previously cataloged. It enhances our understanding of regional ancestry, the spread of languages, the effects of climate change on populations, and the evolutionary history of genetic variants.

Thyroid nodules are extremely prevalent among older adults, and pose a challenge due to the frequency in which they are incidentally encountered. Approximately 5% of all nodules are malignant. Ultrasound is the first line tool to evaluate thyroid nodules, and can help identify nodules that are high-risk for malignancy. Fine needle aspiration (FNA) is an excellent low-risk procedure used to evaluate suspicious thyroid nodules and identify thyroid malignancy. It is performed with a 22-27-gauge needle under ultrasound guidance. Core needle biopsy (CNB) is usually not required; however, it can be helpful if FNA is non-diagnostic or inconclusive. On-site pathologist evaluation can help determine which patients need additional sampling. CNB is usually performed with a trocar technique using an 18-gauge biopsy device under ultrasound guidance. Complications from thyroid biopsy are rare, and the most common complications are discomfort, small to moderate hematoma, and insufficient sampling. Although rare, a rapidly expanding large hematoma can cause airway compression requiring intubation and surgery to preserve the airway and achieve hemostasis. Following biopsy, approximately 10.8% of thyroid nodules will require surgical excision.

The genomes of present-day humans outside Africa originated almost entirely from a single migration out ~50,000-70,000 years ago[1, 2], followed by mixture with Neanderthals contributing ~2% to all non-Africans [3, 4]. However, the details of this initial migration remain poorly-understood because no ancient DNA analyses are available from this key time period, and interpretation of present-day autosomal data is complicated due to subsequent population movements/reshaping [5]. One locus, however, does retain male-specific information from this early period: the Y-chromosome, where a detailed calibrated phylogeny has been constructed [6]. Three present-day Y lineages were carried by the initial migration: the rare haplogroup D, the moderately rare C, and the very common FT lineage which now dominates most non-African populations [6, 7]. We show that phylogenetic analyses of haplogroup C, D and FT sequences, including very rare deep-rooting lineages, together with phylogeographic analyses of ancient and present-day non-African Y-chromosomes, all point to East/South-east Asia as the origin 50,000-55,000 years ago of all known non-African male lineages (apart from recent migrants). This observation contrasts with the expectation of a West Eurasian origin predicted by a simple model of expansion from a source near Africa [8, 9], and can be interpreted as resulting from extensive genetic drift in the initial population or replacement of early western lineages from the east, thus informing and constraining models of the initial expansion.

Integrating Multiple Materials (MM) into large-scale Additive Manufacturing (AM) is a key for various industrial applications wishing to incorporate site-specific properties into geometrically complex designs that are difficult to manufacture with traditional techniques. Printing with multiple materials is typically accomplished by using layers as natural material boundaries, but having the capability to switch between materials within a single layer without pausing would further expand MM possibilities. This study used Cincinnati Incorporated’s Big Area Additive Manufacturing (BAAM) system to explore material transitions with a novel dual-hopper that enables in-situ material blending of a pelletized feedstock. Constructing MM and functionally graded material (FGM) structures requires depositing a specific material composition at a specific geometric location to achieve a desired performance. Accurately implementing this with the BAAM’s blended extrusion system requires a thorough understanding of the transition between distinct material compositions. This study characterizes a step-change transition between neat acrylonitrile butadiene styrene (ABS) and carbon fiber-reinforced ABS. Three distinct techniques were compared for analyzing the fiber content, and the transition zone between materials was characterized as a function of transition direction. The transition process was consistent to within 0.7 wt% carbon fiber variation between different layers and prints. The transition between materials was found to be directionally dependent, with ABS to CF/ABS having a transition length of 3.5 m compared to 3.2 m for CF/ABS to ABS. Furthermore, the transition from Material A to Material B was found to be repeatable with a possible variance in transition length of 0.3 m.

Understanding human genetic diversity in Africa is important for interpreting the evolution of all humans, yet vast regions in Africa, such as Chad, remain genetically poorly investigated. Here, we use genotype data from 480 samples from Chad, the Near East, and southern Europe, as well as whole-genome sequencing from 19 of them, to show that many populations today derive their genomes from ancient African-Eurasian admixtures. We found evidence of early Eurasian backflow to Africa in people speaking the unclassified isolate Laal language in southern Chad and estimate from linkage-disequilibrium decay that this occurred 4,750–7,200 years ago. It brought to Africa a Y chromosome lineage (R1b-V88) whose closest relatives are widespread in present-day Eurasia; we estimate from sequence data that the Chad R1b-V88 Y chromosomes coalesced 5,700–7,300 years ago. This migration could thus have originated among Near Eastern farmers during the African Humid Period. We also found that the previously documented Eurasian backflow into Africa, which occurred ∼3,000 years ago and was thought to be mostly limited to East Africa, had a more westward impact affecting populations in northern Chad, such as the Toubou, who have 20%–30% Eurasian ancestry today. We observed a decline in heterozygosity in admixed Africans and found that the Eurasian admixture can bias inferences on their coalescent history and confound genetic signals from adaptation and archaic introgression.

Summary Bayesian inference is one of the most popular tools for uncertainty analysis in hydrological modeling. While much emphasis has been placed on the selection of appropriate likelihood functions within Bayesian hydrology, few researchers have evaluated the importance of the prior distribution in deriving appropriate posterior distributions. This paper describes tools for the evaluation of parameter sensitivity to the prior distribution to provide guidelines for defining meaningful priors. The tools described here consist of two measurements, the Kullback-Leibler Divergence (KLD) and the prior information elasticity. The Kullback-Leibler Divergence (KLD) is applied to calculate differences between the prior and posterior distributions for different cases. The prior information elasticity is then used to quantify the responsiveness of the KLD values to the change of prior distributions and length of available data. The tools are demonstrated via a Bayesian framework using an MCMC algorithm for a conceptual hydrologic model with both synthetic and real cases. The results of the application of this toolkit suggest the prior distribution can have a significant impact on the posterior distribution and should be more routinely assessed in hydrologic studies.

Summary Australia was one of the earliest regions outside Africa to be colonized by fully modern humans, with archaeological evidence for human presence by 47,000 years ago (47 kya) widely accepted [1, 2]. However, the extent of subsequent human entry before the European colonial age is less clear. The dingo reached Australia about 4 kya, indirectly implying human contact, which some have linked to changes in language and stone tool technology to suggest substantial cultural changes at the same time [3]. Genetic data of two kinds have been proposed to support gene flow from the Indian subcontinent to Australia at this time, as well: first, signs of South Asian admixture in Aboriginal Australian genomes have been reported on the basis of genome-wide SNP data [4]; and second, a Y chromosome lineage designated haplogroup C∗, present in both India and Australia, was estimated to have a most recent common ancestor around 5 kya and to have entered Australia from India [5]. Here, we sequence 13 Aboriginal Australian Y chromosomes to re-investigate their divergence times from Y chromosomes in other continents, including a comparison of Aboriginal Australian and South Asian haplogroup C chromosomes. We find divergence times dating back to ∼50 kya, thus excluding the Y chromosome as providing evidence for recent gene flow from India into Australia., Graphical Abstract, Highlights • We have sequenced 13 Aboriginal Australian Y chromosomes • These diverged from Y chromosomes in other continents around 50,000 years ago • They diverged from Papua New Guinean Y chromosomes soon after this • We find no evidence for Holocene male gene flow to Australia from South Asia, Bergström et al. show that Aboriginal Australian Y chromosomes diverged from Eurasian, including South Asian, Y chromosomes ∼50,000 years ago. This is around the time that Australia was first populated and thus disproves the previous hypothesis of prehistoric Y chromosome gene flow from India ∼5,000 years ago.

In this work, large-scale multimaterial preforms produced by additive manufacturing (AM) underwent compression molding (CM) to produce high-performance thermoplastic composites reinforced with short carbon fibers. AM and CM techniques were integrated to control the fiber orientation (microstructure) and to reduce void content for the improved mechanical performance of the composite. The new integrated manufacturing technique is termed “additive manufacturing-compression molding” (AM-CM). For the present study, the most common materials were used for large-scale printing, i.e., acrylonitrile butadiene styrene (ABS), carbon fiber (CF)–filled ABS (CF/ABS) and glass fiber (GF)–filled ABS (GF/ABS). Three different manufacturing processes; (a) AM (b) extrusion compression molding (ECM), and (c) AM-CM were used to prepare four different panel configurations: (1) neat ABS, (2) CF/ABS, (3) overmold (CF/ABS over neat ABS), and (4) sandwich (neat ABS between two CF/ABS layers). The mechanical properties (tensile and flexural strength and modulus, and Izod impact energy) of samples prepared via all three manufacturing processes were compared. X-ray microcomputer tomography was employed to evaluate the fiber orientation distribution and the volumetric porosity content. The preform maintained high fiber alignment (≈ 82% of fibers within the range of 0–20° in the deposition direction), and the volumetric porosity was reduced by 50% from 3.79% to 1.91% after compression. The alignment of long pores along the deposition direction was also observed. The mechanical properties are discussed with correlation to the fiber alignment and void content in the samples. CF/ABS samples prepared by AM-CM showed significant improvement of 11.15%, 35.27%, 28.6%, and 74.3% in the tensile strength, tensile modulus, flexural strength, and flexural modulus, respectively, when compared with samples prepared by ECM. Unique aspects of this study are the demonstration of large-scale multimaterial AM and the use of multimaterials as preforms to make high-performance composites.

Increasing the fuel burnup limit in light water reactors is sought to enhance fuel cycle economics and requires establishing a technical basis. Experimental observations of severe fuel fragmentation under loss-of-coolant-accident conditions at Halden and Studsvik had raised the need for additional considerations during the development of this technical basis. These test data suggested that the burnup threshold for high burnup fuel fragmentation may be influenced by pre-transient power. Additional loss-of-coolant-accident test data is therefore valuable to complement these tests and enhance the current state of understating. Oak Ridge National Lab has developed the Severe Accident Test Station capable of examining the oxidation kinetics and accident response of irradiated fuel and cladding materials for design basis accident and beyond design basis accident scenarios. Severe Accident Test Station provides various temperature profiles, steam, and the thermal shock conditions necessary for integral loss of coolant accident testing, defueled oxidation quench testing, and high-temperature beyond design basis accident testing. Severe Accident Test Station has been successfully installed and demonstrated in the Irradiated Fuels Examination Laboratory at Oak Ridge National Lab. Furthermore, descriptions of the in-cell re-fabrication capabilities and assembly of the loss-of-coolant-accident test train are provided. Installation of the Severe Accident Test Station system and in-cell re-fabrication restores United States capability to examine postulated and extended loss-of-coolant-accident conditions on spent fuel and cladding and provides a platform for evaluating advanced fuel and accident-tolerant fuel cladding concepts. Lastly, three in-cell integral loss-of-coolant-accident test were performed in the Severe Accident Test Station and compared to the Nuclear Regulatory Commission sponsored loss-of-coolant-accident test as well as the original loss-of-coolant-accident test performed at Argonne National Lab. The results of these tests as well as all publicly available integral loss-of-coolant-accident test were used to validate a threshold for high burnup fuel fragmentation.