Trichoblastic carcinosarcoma in a 34-year-old woman with histopathologic and molecular analysis, including re-demonstration of a CDKN2A p.(R58*) mutation.

Trichoblastic carcinosarcomas are rare, adnexal-type cutaneous carcinosarcomas that are thought to be related histogenetically to trichoblastomas, yet in which both the epithelial and stromal components show features of malignancy. Ten cases have been described in the literature thus far, with a predilection for the head and neck of older males. We present a case of cutaneous carcinosarcoma in sun-damaged skin of a 34-year-old woman showing features of a trichoblastic carcinosarcoma, with histopathologic analysis along with targeted next-generation sequencing of 50 cancer-associated genes. Two pathogenic variants in TP53 were identified, p.(R158C), p.(R273P), along with a likely pathogenic variant CDKN2A, p.(R58*). In particular, it is noted that the CDKN2A p.(R58*) missense mutation has been described in two previous cases of cutaneous carcinosarcomas, including a case of trichoblastic carcinosarcoma.

Correction: Macrophage Colony Stimulating Factor Derived from CD4+ T Cells Contributes to Control of a Blood-Borne Infection.

[This corrects the article DOI: 10.1371/journal.ppat.1006046.].

Macrophage Colony Stimulating Factor Derived from CD4+ T Cells Contributes to Control of a Blood-Borne Infection.

Dynamic regulation of leukocyte population size and activation state is crucial for an effective immune response. In malaria, Plasmodium parasites elicit robust host expansion of macrophages and monocytes, but the underlying mechanisms remain unclear. Here we show that myeloid expansion during P. chabaudi infection is dependent upon both CD4+ T cells and the cytokine Macrophage Colony Stimulating Factor (MCSF). Single-cell RNA-Seq analysis on antigen-experienced T cells revealed robust expression of Csf1, the gene encoding MCSF, in a sub-population of CD4+ T cells with distinct transcriptional and surface phenotypes. Selective deletion of Csf1 in CD4+ cells during P. chabaudi infection diminished proliferation and activation of certain myeloid subsets, most notably lymph node-resident CD169+ macrophages, and resulted in increased parasite burden and impaired recovery of infected mice. Depletion of CD169+ macrophages during infection also led to increased parasitemia and significant host mortality, confirming a previously unappreciated role for these cells in control of P. chabaudi. This work establishes the CD4+ T cell as a physiologically relevant source of MCSF in vivo; probes the complexity of the CD4+ T cell response during type 1 infection; and delineates a novel mechanism by which T helper cells regulate myeloid cells to limit growth of a blood-borne intracellular pathogen.

No clinical differences between anteromedial portal and transtibial technique for femoral tunnel positioning in anterior cruciate ligament reconstruction: a prospective randomized, controlled trial.

PURPOSE: The anteromedial (AMP) portal technique was introduced to position the femoral tunnel in anterior cruciate ligament (ACL) reconstruction to more closely replicate the original ACL footprint compared to the transtibial (TT) approach. Few randomized trials have evaluated differences in these techniques with respect to clinical outcomes. The purpose of this study was to determine if there are any differences in clinical outcome between the AMP and TT approaches. METHODS: This is a single-blinded, prospective, randomized controlled trial. Participants were randomized to undergo ACL reconstruction using the AMP or TT approach. The primary outcome measure was the ACL quality of life (ACL-QOL), and secondary outcomes were the IKDC knee assessment, side-to-side difference in anterior-posterior knee laxity (KT-1000) and tunnel orientation (X-ray findings) at preoperative, 3, 6, 12, and 24 months postoperative. Statistical comparisons were performed using a series of t tests for independent groups with equal variance. RESULTS: Ninety-six participants were consented and randomized between 2007 and 2011 with eight excluded postrandomization. Mean (SD) preoperative ACL-QOL was 33 (13) for TT and 36 (17) for AMP and improved significantly (p < 0.001) in both groups to 79 (18) and 78 (18) at 24 months postoperative, respectively. The preoperative median IKDC grade for both groups was C and improved similarly in both groups at 24 months (n.s.). There was no side-to-side difference in knee laxity based on KT-1000 measurements with a mean (SD) 1 (3) mm between affected and unaffected limbs in the TT group compared to 1 (3) mm for the AMP group. A significant difference was found in femoral tunnel orientation with the AMP group at 43° (7) and the TT group 58° (8) in the coronal plane (p < 0.001). CONCLUSION: No differences in clinical outcome were found when comparing AMP to TT in primary ACL reconstruction using a STG graft. This prospective randomized controlled trial suggests surgeons can use either method without significantly compromising clinical outcome. LEVEL OF EVIDENCE: I.

Solution-Processed Carbon Nanotube True Random Number Generator.

With the growing adoption of interconnected electronic devices in consumer and industrial applications, there is an increasing demand for robust security protocols when transmitting and receiving sensitive data. Toward this end, hardware true random number generators (TRNGs), commonly used to create encryption keys, offer significant advantages over software pseudorandom number generators. However, the vast network of devices and sensors envisioned for the "Internet of Things" will require small, low-cost, and mechanically flexible TRNGs with low computational complexity. These rigorous constraints position solution-processed semiconducting single-walled carbon nanotubes (SWCNTs) as leading candidates for next-generation security devices. Here, we demonstrate the first TRNG using static random access memory (SRAM) cells based on solution-processed SWCNTs that digitize thermal noise to generate random bits. This bit generation strategy can be readily implemented in hardware with minimal transistor and computational overhead, resulting in an output stream that passes standardized statistical tests for randomness. By using solution-processed semiconducting SWCNTs in a low-power, complementary architecture to achieve TRNG, we demonstrate a promising approach for improving the security of printable and flexible electronics.

Large-area, low-voltage, antiambipolar heterojunctions from solution-processed semiconductors.

The emergence of semiconducting materials with inert or dangling bond-free surfaces has created opportunities to form van der Waals heterostructures without the constraints of traditional epitaxial growth. For example, layered two-dimensional (2D) semiconductors have been incorporated into heterostructure devices with gate-tunable electronic and optical functionalities. However, 2D materials present processing challenges that have prevented these heterostructures from being produced with sufficient scalability and/or homogeneity to enable their incorporation into large-area integrated circuits. Here, we extend the concept of van der Waals heterojunctions to semiconducting p-type single-walled carbon nanotube (s-SWCNT) and n-type amorphous indium gallium zinc oxide (a-IGZO) thin films that can be solution-processed or sputtered with high spatial uniformity at the wafer scale. The resulting large-area, low-voltage p-n heterojunctions exhibit antiambipolar transfer characteristics with high on/off ratios that are well-suited for electronic, optoelectronic, and telecommunication technologies.

Subnanowatt carbon nanotube complementary logic enabled by threshold voltage control.

In this Letter, we demonstrate thin-film single-walled carbon nanotube (SWCNT) complementary metal-oxide-semiconductor (CMOS) logic devices with subnanowatt static power consumption and full rail-to-rail voltage transfer characteristics as is required for logic gate cascading. These results are enabled by a local metal gate structure that achieves enhancement-mode p-type and n-type SWCNT thin-film transistors (TFTs) with widely separated and symmetric threshold voltages. These complementary SWCNT TFTs are integrated to demonstrate CMOS inverter, NAND, and NOR logic gates at supply voltages as low as 0.8 V with ideal rail-to-rail operation, subnanowatt static power consumption, high gain, and excellent noise immunity. This work provides a direct pathway for solution processable, large area, power efficient SWCNT advanced logic circuits and systems.

Aerosol jet printed, low voltage, electrolyte gated carbon nanotube ring oscillators with sub-5 µs stage delays.

A central challenge for printed electronics is to achieve high operating frequencies (short transistor switching times) at low supply biases compatible with thin film batteries. In this report, we demonstrate partially printed five-stage ring oscillators with >20 kHz operating frequencies and stage delays <5 µs at supply voltages below 3 V. The fastest ring oscillator achieved 1.2 µs delay time at 2 V supply. The inverter stages in these ring oscillators were based on ambipolar thin film transistors (TFTs) employing semiconducting, single-walled carbon nanotube (CNT) networks and a high capacitance (∼1 µF/cm(2)) ion gel electrolyte as the gate dielectric. All materials except the source and drain electrodes were aerosol jet printed. The TFTs exhibited high electron and hole mobilities (∼20 cm(2)/(V s)) and ON/OFF current ratios (up to 10(5)). Inverter switching times t were systematically characterized as a function of transistor channel length and ionic conductivity of the gel dielectric, demonstrating that both the semiconductor and the ion gel play a role in switching speed. Quantitative scaling analysis suggests that with suitable optimization low voltage, printed ion gel gated CNT inverters could operate at frequencies on the order of 1 MHz.

Computed Tomography Images of a Benign Case of Gastric Pneumatosis in a Returning Traveler.

A 70-year-old male presented to the emergency department with travel-associated vomiting, diarrhea, and abdominal pain. He was found to have gastric pneumatosis on computed tomography. His serum lactic acid level was within normal limits, and he had a benign clinical course.  Gastric pneumatosis can be found in a wide spectrum of clinical situations, from benign to life-threatening. Causes can include ischemia, infections with gas-producing organisms (emphysematous gastritis), or various situations that result in increased intraluminal pressure. As this patient had not recently undergone any endoscopic procedures and had a benign presentation and clinical course, the cause, in this case, is presumed to be related to vigorous retching during a bout of traveler's gastroenteritis.

Stress enhances aggression in male rats with genetic stress hyper-reactivity.

The current study investigated stress-induced aggressive behavior in the resident-intruder test in males of the genetically stress hyper-reactive Wistar Kyoto More Immobile (WMI), and the nearly isogenic, control Wistar Kyoto Less Immobile (WLI) strains. Tests were carried out against same-age intruders during adolescence, and same-age and juvenile intruders in adulthood. In adolescence and adulthood, prior acute restraint stress decreased social interactions and decreased aggressive behaviors of adolescents and adult WLIs. However, prior stress precipitated aggression in the adult WMI males toward both same-age, and juvenile intruders compared with control WMIs and WLIs. Trunk blood levels of testosterone and androstenedione increased in stressed WLIs, but not in WMIs, suggesting no direct role of androgens in the increased aggression of WMIs. Expressions of aggression-relevant genes showed patterns commensurate with being causative in aggressive behavior. The methyl-CpG binding protein 2 was lower in the frontal cortex of control WMIs, and in the amygdala of stressed WMIs compared with their respective WLIs. Frontal cortex expression of vasopressin receptor 1a and serotonin transporter increased, solely in WMI males after stress. As behaviors were the same toward same-age and non-threatening juvenile intruders, the stress-induced increase in confrontational behavior of the adult WMI male was not because of enhanced fear or anxiety. These results suggest that genetic stress hyper-reactivity is a risk factor for stress-induced increases in aggression in males. Additionally, as known aggression-related genes showed expression patterns paralleling aggressive behavior, this model system could identify novel molecular pathways leading to stress-enhanced aggression.

3SAT on an all-to-all-connected CMOS Ising solver chip.

This work solves 3SAT, a classical NP-complete problem, on a CMOS-based Ising hardware chip with all-to-all connectivity. The paper addresses practical issues in going from algorithms to hardware. It considers several degrees of freedom in mapping the 3SAT problem to the chip-using multiple Ising formulations for 3SAT; exploring multiple strategies for decomposing large problems into subproblems that can be accommodated on the Ising chip; and executing a sequence of these subproblems on CMOS hardware to obtain the solution to the larger problem. These are evaluated within a software framework, and the results are used to identify the most promising formulations and decomposition techniques. These best approaches are then mapped to the all-to-all hardware, and the performance of 3SAT is evaluated on the chip. Experimental data shows that the deployed decomposition and mapping strategies impact SAT solution quality: without our methods, the CMOS hardware cannot achieve 3SAT solutions on SATLIB benchmarks. Under the assumption of some hardware improvements, our chip-based 3SAT solver demonstrates a remarkable 250 × acceleration compared to Tabu search in dwave-hybrid on a CPU.

Small RNA sequencing of small extracellular vesicles secreted by umbilical cord mesenchymal stem cells following replicative senescence.

BACKGROUND: Umbilical cord mesenchymal stem cells (UCMSC) are subsets of multipotent stem cells involved in immune modulation, tissue regeneration, and antimicrobial defense. Cellular senescence is associated with the onset of aging-related diseases and small extracellular vesicles (sEVs) are important mediators of senescence and aging. OBJECTIVE: However, little is known about the role and function of microRNAs (miRNAs) carried by UCMSC-derived sEVs. To analyze the expression profiles of miRNAs secreted by senescent UCMSC, small RNA sequencing of the miRNAs within the sEVs was performed in this study. METHODS: UCMSC cultures underwent serial passaging beyond passage number 20 to achieve replicative senescence, which was confirmed by various methods, including increased senescence-associated ß-gal staining and cytokine secretion levels. sEVs derived from non-senescent and senescent UCMSC were isolated and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblot analysis. RESULTS: Small RNA sequencing of the miRNAs within the sEVs revealed senescence-associated differences in the miRNA composition, as shown by the upregulation of miR-122-5p and miR-146a-5p, and downregulation of miR-125b-5p and miR-29-3p. In addition, total RNA sequencing analysis showed that PENK, ITGA8, and TSIX were upregulated, whereas AKR1B10, UNC13D, and IL21R were downregulated by replicative senescence in UCMSC. In sEVs, upregulated genes were linked to downregulated miRNAs, and vice versa. In the gene-concept network analysis, five gynecologic terms were retrieved. CONCLUSIONS: The study provides an insight into the cellular characteristics of UCMSC following replicative senescence and emphasizes the importance of monitoring passage numbers of UCMSC for further therapeutic use.

Heart Failure Among Patients with Multiple Myeloma Treated with Carfilzomib-Based Versus Non-Carfilzomib-Based Regimens in the United States by Race.

BACKGROUND: Carfilzomib treatment for multiple myeloma (MM) can increase heart failure risk. Whether this risk differs by race is unknown. PATIENTS AND METHODS: We sought to estimate the incidence rates (IRs) of heart failure hospitalization among mostly 65-years-and-older US patients with MM by race treated with carfilzomib- and non-carfilzomib-based regimens in the real-world using Centers for Medicare & Medicaid Services Medicare Fee-for-Service data, Optum Clinformatics Data Mart, and Humana Research Database. The risk of heart failure hospitalization associated with a carfilzomib-based regimen was evaluated using propensity score matching among Black and White patients receiving second or later lines of therapy. RESULTS: Most patient-episodes (88%) were in persons 65 years or older for the 3 cohorts combined. The IR (95% CI) of heart failure hospitalization was higher for patient-episodes treated with a carfilzomib-based regimen than those with a non-carfilzomib-based regimen for both White (14.5 [12.2-17.0] vs. 10.7 [10.3-11.2] events per person-years) and Black patients (15.8 [10.1-23.5] vs. 12.1 [10.9-13.4] events per person-years) in the Medicare cohort. After propensity score matching, the hazard ratio (95% CI) of increased heart failure hospitalization comparing carfilzomib-based to non-carfilzomib-based regimens for White patients (1.6 [1.3-2.0]) was similar to that of Black patients (1.7 [1.0-2.9]) in the Medicare Database, and in the Humana Database (1.4 [0.8-2.6] and 1.2 [0.4-3.5], respectively). CONCLUSION: Although the IR of heart failure among patients with MM treated with a carfilzomib-based regimen was slightly higher, no evidence suggested the relative risk was different between White and Black patients with MM.

Infection rates following urologic prosthetic revision without replacement of any device components compared to partial or complete device exchange: a single-center retrospective cohort study.

Urologic implant revision carries a higher infection risk than virgin implantation. Historically, exchanging device components at the time of revision was performed to reduce infection risk. We hypothesize that revision without replacement of any parts of the device may not be associated with increased infection risk. A single-center, retrospective cohort study was performed on patients undergoing urologic implant revision from 2000 to 2021. Revisions involving exchange of any/all device components (+CE) were compared to revisions without exchange of any components (-CE). The primary outcome was infection or erosion within 12 weeks of revision. Infection rates were compared using Fischer exact test. Infection-free survival (IFS) was compared with Kaplan-Meier (KM) log-rank test and Cox proportional hazards (CPH) model. 551 revisions were included, including 497 revisions with CE and 54 without CE. Among those with at least 12 weeks follow-up, no difference was seen in infection rates within 12 weeks of revision [-CE 3/39 (7.7%) vs. +CE 10/383 (2.6%)], p = 0.109). In addition, IFS was comparable between groups (log-rank test p = 0.22, HR for -CE 1.65 (0.65-4.21). Revision surgery for IPP or AUS without CE may not present an elevated risk of infection in the properly selected patient.

A new allele, HLA-C*08:228, identified by sequence-based typing in a Korean individual.

The new allele C*08:228 showed one nucleotide difference from C*08:01:01 in codon 36 (TTC -> TTG).

GeNVoM: Read Mapping Near Non-Volatile Memory.

DNA sequencing is the physical/biochemical process of identifying the location of the four bases (Adenine, Guanine, Cytosine, Thymine) in a DNA strand. As semiconductor technology revolutionized computing, modern DNA sequencing technology (termed Next Generation Sequencing, NGS) revolutionized genomic research. As a result, modern NGS platforms can sequence hundreds of millions of short DNA fragments in parallel. The sequenced DNA fragments, representing the output of NGS platforms, are termed reads. Besides genomic variations, NGS imperfections induce noise in reads. Mapping each read to (the most similar portion of) a reference genome of the same species, i.e., read mapping, is a common critical first step in a diverse set of emerging bioinformatics applications. Mapping represents a search-heavy memory-intensive similarity matching problem, therefore, can greatly benefit from near-memory processing. Intuition suggests using fast associative search enabled by Ternary Content Addressable Memory (TCAM) by construction. However, the excessive energy consumption and lack of support for similarity matching (under NGS and genomic variation induced noise) renders direct application of TCAM infeasible, irrespective of volatility, where only non-volatile TCAM can accommodate the large memory footprint in an area-efficient way. This paper introduces GeNVoM, a scalable, energy-efficient and high-throughput solution. Instead of optimizing an algorithm developed for general-purpose computers or GPUs, GeNVoM rethinks the algorithm and non-volatile TCAM-based accelerator design together from the ground up. Thereby GeNVoM can improve the throughput by up to 3.67×; the energy consumption, by up to 1.36×, when compared to an ASIC baseline, which represents one of the highest-throughput implementations known.

Humoral and Cellular Immune Responses to Vector, Mix-and-Match, or mRNA Vaccines against SARS-CoV-2 and the Relationship between the Two Immune Responses.

We investigated how differences in age, sex, or vaccine type can affect humoral and cellular immune responses after vaccination with vector (ChAdOx1 nCoV-19), mix-and-match (first, ChAdOx1 nCoV-19, and second, BNT162b2), or mRNA (BNT162b2 or mRNA-1273) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Venous blood was collected from 573 subjects (vector, 396; mix-and-match, 96; and mRNA, 81) before the first vaccination (T0), 7 to 8 weeks (vector) or 3 to 4 weeks (mRNA) after the first vaccination (T1), and 3 to 4 weeks after the second vaccination (T2). The humoral and cellular immune responses were evaluated using Elecsys anti-SARS-CoV-2 (Roche), Alinity SARS-CoV-2 IgG II Quant (Abbott), cPass SARS-CoV-2 neutralization antibody detection (GenScript), and QuantiFERON SARS-CoV-2 (Qiagen) kits. At T1, the levels of the receptor-binding domain antibodies (RBD Ab) and neutralizing antibodies (NAb) decreased with aging, but interferon gamma release (IGR) levels increased. The RBD Ab, NAb, and IGR levels were higher in females than in males at T1 and T2. The NAb levels were higher in the mix-and-match and mRNA vaccine groups than in the vector vaccine group at T2. The RBD Ab and IGR levels were higher in the mRNA vaccine group than in the vector or mix-and-match vaccine groups at T2. The optimal cutoffs for RBD Ab and NAb, which were used to determine the presence of T cell responses, were 5.7 binding antibody units per milliliter (BAU mL-1) and 12.0 IU mL-1, respectively. Age, sex, and vaccine type affected the humoral and cellular immune responses, and T cell responses could be estimated from RBD Ab and NAb levels. IMPORTANCE There have been few studies that comprehensively evaluated factors affecting immune responses and the correlation between humoral and cellular immune responses after vector, mix-and-match, and mRNA vaccines against SARS-CoV-2. Therefore, we analyzed the effects of age, sex, and the different vaccine regimens on the immune responses to vaccination against SARS-CoV-2. The correlation between humoral and cellular immune responses and the cutoffs were derived for RBD antibodies and neutralizing antibodies to predict the presence of the cellular immune responses. In this comprehensive study, we demonstrated that there were differences in the immune responses induced after vaccination depending on the age and sex of an individual. Among the three vaccine regimens, the mix-and-match and mRNA vaccines induced the most robust immune responses. Finally, the proposed optimal cutoffs for RBD and neutralizing antibodies may be useful for predicting cellular immune responses when assays for cellular immune responses are not available.

Identification of large offspring syndrome during pregnancy through ultrasonography and maternal blood transcriptome analyses.

In vitro production (IVP) of embryos in cattle can result in large/abnormal offspring syndrome (LOS/AOS) which is characterized by macrosomia. LOS can cause dystocia and lead to the death of dam and calf. Currently, no test exists to identify LOS pregnancies. We hypothesized that fetal ultrasonography and/or maternal blood markers are useful to identify LOS. Bovine fetuses were generated by artificial insemination (control) or IVP. Fetal ultrasonographies were taken on gestation D55 (D55) and fetal collections performed on D56 or D105 (gestation in cattle ≈ D280). IVP fetuses weighing ≥ 97 percentile of the control weight were considered LOS. Ultrasonography results show that the product of six D55 measurements can be used to identify extreme cases of LOS. To determine whether maternal blood can be used to identify LOS, leukocyte mRNA from 23 females was sequenced. Unsupervised hierarchical clustering grouped the transcriptomes of the two females carrying the two largest LOS fetuses. Comparison of the leukocyte transcriptomes of these two females to the transcriptome of all other females identified several misregulated transcripts on gestation D55 and D105 with LOC783838 and PCDH1 being misregulated at both time-points. Together our data suggest that LOS is identifiable during pregnancy in cattle.

An automated COVID-19 triage pipeline using artificial intelligence based on chest radiographs and clinical data.

While COVID-19 diagnosis and prognosis artificial intelligence models exist, very few can be implemented for practical use given their high risk of bias. We aimed to develop a diagnosis model that addresses notable shortcomings of prior studies, integrating it into a fully automated triage pipeline that examines chest radiographs for the presence, severity, and progression of COVID-19 pneumonia. Scans were collected using the DICOM Image Analysis and Archive, a system that communicates with a hospital's image repository. The authors collected over 6,500 non-public chest X-rays comprising diverse COVID-19 severities, along with radiology reports and RT-PCR data. The authors provisioned one internally held-out and two external test sets to assess model generalizability and compare performance to traditional radiologist interpretation. The pipeline was evaluated on a prospective cohort of 80 radiographs, reporting a 95% diagnostic accuracy. The study mitigates bias in AI model development and demonstrates the value of an end-to-end COVID-19 triage platform.

Angioedema Secondary to tPA Use in Acute Ischemic Stroke Patient with Hypertension: A Case Report.

INTRODUCTION: A well-documented complication of administering tissue plasminogen activator (tPA) in stroke patients is acute intracranial bleeding. A lesser known but still significant complication is angioedema secondary to tPA administration, which can develop in certain individuals with risk factors such as angiotensin converting enzyme (ACE) inhibitor use and location of the stroke. Knowing the potential for this life-threatening complication and being prepared for its proper management is vital for emergency physicians. CASE REPORT: We report a 53-year-old Black female who presented to the emergency department with sudden onset of slurred speech and a facial droop. She was found to have an acute ischemic stroke and tPA was administered. She subsequently developed angioedema. Retrospectively, the patient was found to have risk factors that are thought to predispose patients to tPA-induced angioedema. CONCLUSION: Risk factors associated with angioedema secondary to tPA administration have been documented in patients taking ACE inhibitors, as well as patients who develop strokes in the frontal lobe. While many cases may be mild, some patients may develop life-threatening angioedema. Although this complication does not necessarily contraindicate tPA use, it is prudent for the emergency physician to be vigilant for its development, prepared for its treatment, and to be diligent in assessing the need for control of the patient's airway.