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Summary: Background: We aimed to study the clinical characteristics, myocardial injury, and longitudinal outcomes of COVID-19 vaccine-associated myocarditis (C-VAM). Methods: In this longitudinal retrospective observational cohort multicenter study across 38 hospitals in the United States, 333 patients with C-VAM were compared with 100 patients with multisystem inflammatory syndrome in children (MIS-C). We included patients ≤30 years of age with a clinical diagnosis of acute myocarditis after COVID-19 vaccination based on clinical presentation, abnormal biomarkers and/or cardiovascular imaging findings. Demographics, past medical history, hospital course, biochemistry results, cardiovascular imaging, and follow-up information from April 2021 to November 2022 were collected. The primary outcome was presence of myocardial injury as evidenced by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. Findings: Patients with C-VAM were predominantly white (67%) adolescent males (91%, 15.7 ± 2.8 years). Their initial clinical course was more likely to be mild (80% vs. 23%, p 15 years, OR 2.74 [95% CI: 1.28, 5.83, p = 0.009]) and when C-VAM occurred after the first or second dose as compared to the third dose of mRNA vaccine. Mid-term clinical outcomes of C-VAM at a median follow-up of 178 days (IQR 114–285 days) were reassuring. No cardiac deaths or heart transplantations were reported until the time of submission of this report. LGE persisted in 60% of the patients at follow up. Interpretation: Myocardial injury at initial presentation and its persistence at follow up, despite a mild initial course and favorable mid-term clinical outcome, warrants continued clinical surveillance and long-term studies in affected patients with C-VAM. Funding: The U.S. Food and Drug Administration.

Objective: Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide. Low density lipoprotein cholesterol (LDL-C) contributes to the atherogenic process. However, direct LDL-C (d-LDL) has rarely been estimated by the gold standard method because it is cumbersome and expensive. We aim to evaluate calculated low density lipoprotein (LDL-c) by various equations with reference to directly measured LDL-C in the Pakistani adult population as a cost-effective alternative. Methods: We retrospectively evaluated the validity of seven equations for estimating calculated LDL-C by computing correlation coefficients (r) and Bland Altman plots to assess agreement (mean %) for (d-LDL) and calculated (LDL-c) on all seven equations. Statistical analysis was performed in Stata Statistical Software: Release 17, College Station, TX: StataCorp LLC. Results: We analyzed 247082 direct assays of lipid profiles of adults aged ≥18 years. The mean LDL-C levels computed on Friedewald, de Cordova, Chen, Hattori, Vujovic, Teerakanchana, Sampson equations were 106.8 ± 31.4, 103.7 ± 25.0, 108.6 ± 28.2, 100.1 ± 29.5, 115.2 ± 31.2, 113.1 ± 28.3 and 110.3 ± 30.6 respectively. Friedewald and Hattori equations correlated strongly with direct LDL-C (r = 0.937) for each followed by Sampson (r = 0.935) and Vujovic (r = 0.931). However, the median bias was least for the Friedwald equation (−1.6) compared to the other equations. Conclusion: In contrast to the global literature advocating for the use of newer equations, although the conventional and widely utilized Friedewald equation remains the best alternative for calculated LDL-C estimation in adult Pakistani population.

Traditionally concrete strength determination has been a costly and time-consuming process, relying on periodic laboratory testing using compression tests on concrete-filled cylinders. To address these challenges, an innovative framework has been developed using the Internet of Things (IoT) technology-based low-cost wireless sensors. These sensors have been programmed to integrate with a real-time data monitoring platform using the Firebase cloud computing application. This framework allows remote real-time concrete compressive strength monitoring while reducing the need for on-site laboratory testing. This aspect can ultimately add digital competencies to the construction industry. The IoT-based data is further integrated with the Building Information Modeling (BIM) model of the structure, developing its Digital Twin (DT), which enables the concerned authorities to remotely access the concrete compressive strength parameters, particularly in the early stages. The proposed system presents notable advantages compared to traditional methods by enabling remote real-time monitoring of concrete strength parameters in the BIM environment and facilitating informed decision-making to optimize the construction schedule utilizing the Active BIM system. It serves as a pioneering advancement in internet/remote applications designed to monitor early-age compressive strength. By assisting project managers in timely actions such as formwork removal, post-tensioning, curing termination, and reshores removal, it generates significant cost savings in terms of labor and expedites the completion of construction activities.

Adolescent dating violence and substance use are clinical and public health concerns. Prior meta-analytic studies indicate that about 20% of adolescents reported having experienced physical dating violence (PDV) and 10% reported sexual dating violence (SDV). This study aims to assess the prevalence of dating violence, and the association between substance use and dating violence among adolescents. Our study population is derived from the 2019 Youth Risk Behavior Surveillance System (YRBSS)a cross-sectional, nationally representative survey of United States (U.S) adolescents. The sample comprised 13,677 adolescents between the ages of 13–19 years currently enrolled in school. Descriptive analysis estimated the prevalence of dating violence and substance use. Multiple logistic regression adjusted for confounders of the association between substance use and dating violence. The confounders adjusted for include sex, school grade, race, academic grade, and duration of night sleep. The prevalence of PDV and SDV was each 8.2%. Only 2.6% of this nationally representative sample had experienced both PDV and SDV. Adolescents who used three or more substances had 2.1 times higher odds of PDV (OR = 2.10, 95% CI = 1.27–3.47, p

Cholesterol is an essential structural component of all membranes of mammalian cells where it plays a fundamental role not only in cellular architecture, but also, for example, in signaling pathway transduction, endocytosis process, receptor functioning and recycling, or cytoskeleton remodeling. Consequently, intracellular cholesterol concentrations are tightly regulated by complex processes, including cholesterol synthesis, uptake from circulating lipoproteins, lipid transfer to these lipoproteins, esterification, and metabolization into oxysterols that are intermediates for bile acids. Oxysterols have been considered for long time as sterol waste products, but a large body of evidence has clearly demonstrated that they play key roles in central nervous system functioning, immune cell response, cell death, or migration and are involved in age-related diseases, cancers, autoimmunity, or neurological disorders. Among all the existing oxysterols, this review summarizes basic as well as recent knowledge on 25-hydroxycholesterol which is mainly produced during inflammatory or infectious situations and that in turn contributes to immune response, central nervous system disorders, atherosclerosis, macular degeneration, or cancer development. Effects of its metabolite 7α,25-dihydroxycholesterol are also presented and discussed.

CMOS IC technology is encountering limitations due to fabrication challenges, matching characteristics, and the pursuit of miniaturization. These constraints have prompted the exploration of alternative technologies to cater to the demands of the nanoscale realm. Quantum Dot Cellular Automata (QCA) has emerged as a promising candidate for implementing digital systems at the nanoscale. However, given the nascent stage of QCA technology, the risk of defects during fabrication in the nano-regime is a significant concern. Consequently, the development of fault-tolerant circuits and systems becomes pivotal for the practical realization of this technology. In this study, we introduce a fault-tolerant 3-input majority voter (FT-MV3) designed to achieve 100% fault tolerance against single-cell omission and additional-cell defects. We also assess the fault tolerance of this design in the presence of other fabrication defects. Furthermore, our study includes an energy dissipation analysis of the proposed design. Additionally, we present layout designs for fault-tolerant RAM cells, both with and without the Universal, Scalable, and Efficient (USE) clocking scheme. Our findings demonstrate that the USE-based RAM cell design exhibits an impressive fault tolerance of 95.52% against single-cell omission defects, making it a robust choice for the implementation of reliable RAM architectures.

Parahydrogen-Induced Polarization (PHIP) is NMR hyperpolarization technique that has matured from fundamental science to a biomedical tool for production of hyperpolarized MRI contrast agents. The spin order of nascent parahydrogen-derived protons can be employed directly for enhancement of their NMR signals or for polarization transfer to other nuclei in the hydrogenation product. In this work, we study the process of pairwise parahydrogen addition to propylene, which results in symmetric propane molecule with substantially enhanced methyl and methylene NMR signals. Specifically, we have synthesized site-selectively isotopically labeled 3-d-propylene molecule to study polarization dynamics in the resulting monodeuterated propane after pairwise parahydrogen addition. The deuterium presence in the hyperpolarized propane product results in a minute isotope chemical shift effect allowing to distinguish the proton resonances of CH3 and CH2D groups at 600 MHz. Pairwise parahydrogen 1,2-addition to 3-d-propylene was first confirmed by performing the reaction inside a 600 MHz NMR spectrometer, i.e., in the weakly-coupled regime at 14 T, where proton polarization dynamics is restricted to the molecular sites of parahydrogen addition. However, when the pairwise parahydrogen addition is performed in the strongly-coupled regime, i.e., at the Earth's magnetic field, efficient polarization transfer to CH2D protons is readily observed, leading to polarization redistribution between the three inequivalent sites. This finding is important as it sheds light on polarization dynamics in the strongly coupled symmetric spin systems such as propane studied here—the presented results are expected to be applicable to other spin systems such as butane.

Purpose: We aimed to evaluate the cost effectiveness of Favipiravir treatment versus standard of care (SC) in moderately to severely ill COVID-19 patients from the Saudi healthcare payer perspective. Methods: We used the patient-level simulation method to simulate a cohort of 415 patients with moderate to severe COVID-19 disease who were admitted to two Saudi COVID-19 referral hospitals: 220 patients on Favipiravir and 195 patients on SC. We estimated the incremental cost-effectiveness ratio (ICER) of Favipiravir versus SC in terms of the probability to be discharged alive from hospital and the mean time in days to discharge one patient alive. The model was performed twice: first, using unweighted, and second, using weighted clinical and economic data. Weighting using the inverse weight probability method was performed to achieve balance in baseline characteristics. Results: In the unweighted model, base case (probabilistic) ICER estimates favored Favipiravir at savings of Saudi Riyal (SAR)1,611,511 (SAR1,998,948) per 1% increase in the probability of being discharged alive. As to mean time to discharging one patient alive, ICERs favored Favipiravir at savings of SAR11,498 (SAR11,125). Similar results were observed in the weighted model with savings using Favipiravir of SAR1,514,893 (SAR2,453,551) per 1% increase in the probability of being discharged alive, and savings of SAR11,989 (SAR11,277) for each day a patient is discharged alive. Conclusion: From the payer perspective, the addition of Favipiravir in moderately to severely ill COVID-19 patients was cost-savings over SC. Favipiravir was associated with a higher probability of discharging patients alive and lower daily spending on hospitalization than SC.

High-speed networks are utilized to satisfy user demands by using cloud and edge services. Due to the heterogeneous nature of these networks, security, trust, and privacy are the significant challenges for these networks. These networks are vulnerable to various security threats, lack of trustworthy devices, and user privacy concerns due to architectural complexities, diversity of protocols, and dynamic network topologies. This Systematic Literature Review (SLR) explores these networks in terms of technologies, edge and cloud services, security, trust and privacy concerns. Torress-Carrion methodology is used as a guideline to conduct this review to find the recent security, trust and privacy concerns. The attacks related to each area and their solutions are discussed to evaluate their strengths and weaknesses. The various existing technologies explore like Blockchain, encryption, hashing, and fuzzy logic. In addition, the trust evaluation and user privacy provision techniques are also discuss. This SLR also explores the methods designed for different communication layers against the various multilingual passive/active attacks like Sybil, Denial of Service (DoS), Distributed Denial of Service (DDoS), and Man in the Middle (MITM). This SLR will provide a direction to new researchers in the field of security, trust, and privacy to design more efficient and effective solutions to deal with new security challenges.

Until now, many methods have been proposed to treat cancer, such as radiation therapy and drug therapy, but none of them have caused a complete cure for cancer. Heavy metal complexes such as cisplatin are among the compounds used as drugs in chemotherapy against cancer cells. These compounds cause cell death and have anti-cancer properties, but they have side effects. The biochemical mechanism of cisplatin is related to its interaction with DNA through covalent binding. To reduce the toxicity of metallodrugs, new complexes can be designed containing S, S- bidentate ligands such as diethyldithiocarbamate. Moreover, anti-cancer compounds probably interact with proteins, such as HSA, before passing the cancerous cell membrane and DNA as a target. So, the function of proteins and their stabilities are expected to change. In this research, the mode of binding of [Pt (bpy) (amyl.dtc)]NO3 complex with BSA was evaluated by various thermodynamic methods. Negative binding enthalpy and entropy changes amounts show that the connection between the Platinum compound and BSA occurs via the van Der Waals type of hydrogen bond. The negative Gibbs free energy change was obtained through isothermal titration, which showed interaction proceeds spontaneously. Moreover, the emission titration data showed that protein fluorescence quenching by platinum agent titration is static. Binding, quenching constants, and binding site number were obtained by the Stern-Volmer equation, and only one binding site was determined for this interaction. A Scatchard plot with a positive slope shows the Pt agent-BSA formation is proceeding positively cooperative. The kinetic study displayed that the absorption monitoring followed the second-order model. Finally, molecular docking simulation showed that the position of the Pt agent on protein is placed I under region II.

With the advancement in the Internet of Medical Things (IoMT) infrastructure, network security issues have become a serious concern for hospitals and medical facilities. For this, a variety of customized network security tools and frameworks are used to distract several generalized attacks such as botnet-based distributed denial of services attacks (DDoS) and zero-day network attacks. Thus, it becomes difficult to operate routine IoMT services and tasks in between the under-attack scenario. This paper discusses a novel approach named Duo-Secure IoMT framework that uses multi-modal sensory signals’ data to differentiate the attack pattern and routine IoMT devices’ data. The proposed model uses a combination of two techniques such as dynamic Fuzzy C-Means clustering along with customized Bi-LSTM technique that processes sensory medical data securely along with identifying attack patterns within the IoMT network. As a case study, we are using a dataset to evaluate heart disease which consists of 36 attributes and 18940 instances. The performance evaluation shows that the proposed model evaluates a) prediction of heart issues and b) identification of network malware with an individual accuracy of 92.95% and multi-modal joint accuracy of 89.67% in the IoMT-based distributed network environment.

Summary: The NLR protein NLRP12 contributes to innate immunity, but the mechanism remains elusive. Infection of Nlrp12−/− or wild-type mice with Leishmania infantum led to aberrant parasite tropism. Parasites replicated to higher levels in livers of Nlrp12−/− mice than in the livers of WT mice and failed to disseminate to spleens. Most retained liver parasites resided in dendritic cells (DCs), with correspondingly fewer infected DCs in spleens. Furthermore, Nlrp12−/− DCs expressed lower CCR7 than WT DCs, failed to migrate toward CCL19 or CCL21 in chemotaxis assays, and migrated poorly to draining lymph nodes after sterile inflammation. Leishmania-infected Nlpr12−/− DCs were significantly less effective at transporting parasites to lymph nodes than WT DCs. Consistently, adaptive immune responses were also impaired in infected Nlrp12−/− mice. We hypothesize that Nlrp12-expressing DCs are required for efficient dissemination and immune clearance of L. infantum from the site of initial infection. This is at least partly due to the defective expression of CCR7.

The Internet of Medical Things (IoMT) facilitates patients with all-time-connected medical devices through cost-effective solutions and a feeling of comfort with round-the-clock hospital support. The patients who cannot visit hospitals for routine checkups prefer the usage of IoMT devices. The healthcare facilities also rely on the real-time statistics of IoMT machines and diagnose problems and their solutions within a small interval of time. This could only be possible when a robust convergence of technologies is used with IoMT devices. This review study discusses how we may apply the convergence of IoMT devices with trending technologies and focuses on delivering a new dimension of novel IoMT usage through broad multi-homing dense networks. It also discusses various applied machine learning algorithms available in the healthcare industry. It compares a variety of disease predictions and the accuracy of the equipment and decision recommendations. The review study also discusses various IoMT convergence open challenges and opportunities through the labor industry healthcare system.

With tremendous advancements in smart phone industry and IoT devices, edge computing has emerged to provide computational services at edge of the network. As a result, applications can be executed in a distributive manner to meet the latency requirements of applications. Despite these advancements, these devices are still considered to have limited energy, memory and computational resources compared to stationary standalone devices. Mobile edge computing extends mobile cloud computing close to end-users, decreasing latency and bandwidth utilisation by offloading tasks to edge servers. Fog computing places nodes between cloud and edge servers. A challenging approach in these paradigms is establishing offloading decision to edge/fog server, and distributed application execution at run time for heterogeneous devices. This paper reviews execution of resource-intensive tasks on mobile devices in distributed frameworks. The objective is to identify research gaps and highlight new research directions that can be pursued in future. Application execution involves application partitioning, task allocation, task execution and task resumption. In this paper, we propose a separate taxonomy for each step in application execution, reviews state-of-the-art techniques, and analyses critical aspects of application execution in a distributed manner. It further investigates similarities and differences among these techniques based on each step of application execution.

Replicator Neural Network (RNN) is a popular algorithm for anomaly detection, but finding optimal number of hidden layers and then finding optimal number of neurons in each hidden layer is quite a challenging and time-consuming task. Extreme Learning Machines (ELM) are neural networks with single-hidden layer but the learning algorithm is different and faster than back-propagation. ELM-based RNNs solve our problem of determining the number of hidden layers and the learning algorithm is also faster than gradient-descent based RNN. The problem of identifying the optimal number of neurons in the hidden layer can be solved by Garson algorithm. In this work, the author propose an optimal Replicator Neural Network which is optimized using ELM learning and Garson algorithm for anomaly detection. The experimental results show that the proposed method is fast as well as highly accurate.

Objective: : This study aimed to describe the distribution of respiratory pathogens and the occurrence of co-pathogens during the first year of the COVID-19 pandemic. Methods: We used a multiplex polymerase chain reaction (PCR) panel targeting 23 microorganisms to analyze the oro-pharyngeal samples of patients admitted to our hospital with acute respiratory infection (ARI) between March 1, 2020, and February 28, 2021. We matched 40 to 50 patients who were SARS-CoV-2 positive and SARS-CoV-2 negative per month for age and sex. Results: A total of 939 patients with multiplex PCR test results were included in the study. Respiratory pathogens where detected in only 8/476 (1.6%) patients with COVID-19 versus 87/463 (18.7%) patients with non–COVID-19 ARI patients. Diversity and rates of pathogens vastly differed from previous years but showed seasonal variance. Conclusion: Patients with SARS-CoV-2 infection presenting with ARI during the first year of the COVID-19 pandemic demonstrated paucity of respiratory co-pathogens.

Summary: Background: Primary HPV screening, due to its low specificity, requires an additional liquid-based cytology (LBC) triage test. However, even with LBC triage there has been a near doubling in the number of patients referred for colposcopy in recent years, the majority having low-grade disease. Methods: To counter this, a triage test that generates a spatial map of the cervical surface at a molecular level has been developed which removes the subjectivity associated with LBC by facilitating identification of lesions in their entirety. 50 patients attending colposcopy were recruited to participate in a pilot study to evaluate the test. For each patient, cells were lifted from the cervix onto a membrane (cervical cell lift, CCL) and immunostained with a biomarker of precancerous cells, generating molecular maps of the cervical surface. These maps were analysed to detect high-grade lesions, and the results compared to the final histological diagnosis. Findings: We demonstrated that spatial molecular mapping of the cervix has a sensitivity of 90% (95% CI 69-98) (positive predictive value 81% (95% CI 60-92)) for the detection of high-grade disease, and that AI-based analysis could aid disease detection through automated flagging of biomarker-positive cells. Interpretation: Spatial molecular mapping of the CCL improved the rate of detection of high-grade disease in comparison to LBC, suggesting that this method has the potential to decisively identify patients with clinically relevant disease that requires excisional treatment. Funding: CRUK Early Detection Project award, Jordan-Singer BSCCP award, Addenbrooke's Charitable Trust, UK-MRC, Janssen Pharmaceuticals/Advanced Sterilisation Products, and NWO.

Objective: To explore the literature on corona-associated mucormycosis and explain its relevance to dentists and oral surgeons. Methods: A literature search was carried out to identify reported cases on corona-associated mucormycosis since the start of COVID-19 pandemic. Results: A review of literature identified 265 published papers on CAM between March 2020 and September 2021. Careful screening of abstracts and full texts revealed 29 studies reporting case series of CAM and, 27 case reports on CAM. Conclusions: A multitude of factors may be responsible for the alarming rise in the incidence of corona-associated mycosis including reduced access to routine medical services during the pandemic, injudicious use of antibiotics, steroids and nutritional supplements. Risk factors contributing to corona-associated mucormycosis need to be recognized. Dentists and oral surgeons can contribute to early recognition of corona-associated mucormycosis involving the maxilla, and palate. Prioritizing research focus on optimal management of mucormycosis may reduce the morbidity and mortality associated with this debilitating infection.

Abstract Background 3D-time resolved flow (4DF) cardiovascular magnetic resonance (CMR) with retrospective analysis of atrioventricular valve regurgitation (AVVR) allows for internal validation by multiple direct and indirect methods. Limited data exist on direct measurement of AVVR by 4DF CMR in pediatric congenital heart disease (CHD). We aimed to validate direct measurement of the AVVR jet as accurate and reliable compared to the volumetric method (clinical standard by 2D CMR) and as a superior method of internal validation than the annular inflow method. Methods We identified 44 consecutive patients with diverse CHD referred for evaluation of AVVR by CMR. 1.5 T or 3 T scanners, intravenous contrast, and a combination of parallel imaging and compressed sensing were used. Four methods of measuring AVVR volume (RVol) were used: volumetric method (VOL; the clinical standard) = stroke volume by 2D balanced steady-state free precession – semilunar valve forward flow (SLFF); annular inflow method (AIM) = atrioventricular valve forward flow [AVFF] – semilunar valve net flow (SLNF); and direct measurement (JET). AVFF was measured using static and retrospective valve tracking planes. SLFF, SLNF, AVFF, and JET were measured by 4DF phase contrast. Regurgitant fraction was calculated as [RVol/(RVol+SLNF)]× 100. Statistical methods included Spearman, Wilcoxon rank sum test/Student paired t-test, Bland Altman analysis, and intra-class coefficient (ICC), where appropriate. Results Regurgitant fraction by JET strongly correlated with the indirect methods (VOL and AIM) (ρ = 0.73–0.80, p

Mitochondrial dysfunction underlying metabolic disorders such as obesity and diabetes mellitus is strongly associated with cardiac arrhythmias. Murine Pgc-1α−/− hearts replicate disrupted mitochondrial function and model the associated pro-arrhythmic electrophysiological abnormalities. Quantitative PCR, western blotting and histological analysis were used to investigate the molecular basis of the electrophysiological changes associated with mitochondrial dysfunction. qPCR analysis implicated downregulation of genes related to Na+-K+ ATPase activity (Atp1b1), surface Ca2+ entry (Cacna1c), action potential repolarisation (Kcnn1), autonomic function (Adra1d, Adcy4, Pde4d, Prkar2a), and morphological properties (Myh6, Tbx3) in murine Pgc-1α−/− ventricles. Western blotting revealed reduced NaV1.5 but normal Cx43 expression. Histological analysis revealed increased tissue fibrosis in the Pgc-1α−/− ventricles. These present findings identify altered transcription amongst a strategically selected set of genes established as encoding proteins involved in cardiac electrophysiological activation and therefore potentially involved in alterations in ventricular activation and Ca2+ homeostasis in arrhythmic substrate associated with Pgc-1α deficiency. They complement and complete previous studies examining such expression characteristics in the atria and ventricles of Pgc-1 deficient murine hearts.

Background: High-level disinfection protects tens-of-millions of patients from the transmission of viruses on reusable medical devices. The efficacy of high-level disinfectants for preventing human papillomavirus (HPV) transmission has been called into question by recent publications, which if true, would have significant public health implications. Methods: Evaluation of the clinical relevance of these published findings required the development of novel methods to quantify and compare: (i) Infectious titres of lab-produced, clinically-sourced, and animal-derived papillomaviruses, (ii) The papillomavirus dose responses in the newly developed in vitro and in vivo models, and the kinetics of in vivo disease formation, and (iii) The efficacy of high-level disinfectants in inactivating papillomaviruses in these systems. Findings: Clinical virus titres obtained from cervical lesions were comparable to those obtained from tissue (raft-culture) and in vivo models. A mouse tail infection model showed a clear dose-response for disease formation, that papillomaviruses remain stable and infective on fomite surfaces for at least 8 weeks without squames and up to a year with squames, and that there is a 10-fold drop in virus titre with transfer from a fomite surface to a new infection site. Disinfectants such as ortho-phthalaldehyde and hydrogen peroxide, but not ethanol, were highly effective at inactivating multiple HPV types in vitro and in vivo. Interpretation: Together with comparable results presented in a companion manuscript from an independent laboratory, this work demonstrates that high-level disinfectants inactivate HPV and highlights the need for standardized and well-controlled methods to assess HPV transmission and disinfection. Funding: Advanced Sterilization Products, UK-MRC (MR/S024409/1 and MC-PC-13050) and Addenbrookes Charitable Trust

Introduction: Intraoperative imaging and stereotactic navigation in spinal surgery to guide instrumentation placement and tumour resection is well documented. However, image depiction is restricted to high attenuation structures such as osseous tissue and metal objects. Vascular anatomy like major arteries or vascular neoplasm cannot be depicted. We reported angiographically enhancing intraoperative cone-beam imaging (O-arm) to facilitate resection of a craniocervical junction neoplasm that distorted the course of vertebral artery, and discussed the feasibility of this technique. Methods: We performed intraoperative angiography employing the O-arm for image acquisition, and applied the images in S7 Stealth Station to guide tumour resection in an occipitocervical osseous tumour in which the course of the vertebral artery was heavily distorted. Results: Intraoperative findings matched the 3D navigation images demonstrating the V3 and upper V2 segments of the vertebral artery in close proximity to the tumour. Complete en bloc tumour removal was achieved without injury to the adjacent vertebral artery. No intra- or postoperative complications occurred. Conclusion: It is feasible intraoperatively to acquire angiographically enhancing cone-beam imaging of spinal tumour in close proximity to the V3 and upper V2 segments of vertebral artery. It appears to facilitate safe tumour resection by mapping critical vascular structures in the surgical field that is initially occult to direct vision. Such novel use of technique warrants further validation.

Background: We have observed that critically ill patients with COVID-19 are in an extreme hypermetabolic state. This may be a major contributing factor to the extraordinary ventilatory and oxygenation demands seen in these patients. We aimed to quantify the extent of the hypermetabolic state and report the clinical effect of the use of hypothermia to decrease the metabolic demand in these patients. Methods: Mild hypothermia was applied on four critically ill patients with COVID-19 for 48 h. Metabolic rates, carbon dioxide production and oxygen consumption were measured by indirect calorimetry. Results: The average resting energy expenditure (REE) was 299% of predicted. Mild hypothermia decreased the REE on average of 27.0% with resultant declines in CO2 production (VCO2) and oxygen consumption (VO2) by 29.2% and 25.7%, respectively. This decrease in VCO2 and VO2 was clinically manifested as improvements in hypercapnia (average of 19.1% decrease in pCO2 levels) and oxygenation (average of 50.4% increase in pO2). Conclusion: Our case series demonstrates the extent of hypermetabolism in COVID-19 critical illness and suggests that mild hypothermia reduces the metabolic rate, improves hypercapnia and hypoxia in critically ill patients with COVID-19.

Summary: Germline epigenetic factors influence transgenerational inheritance of behavioral traits upon changes in experience and environment. Immune activation due to infection can also modulate brain function, but whether this experience can be passed down to offspring remains unknown. Here, we show that infection of the male lineage with the common human parasite Toxoplasma results in transgenerational behavioral changes in offspring in a sex-dependent manner. Small RNA sequencing of sperm reveals significant transcriptional differences of infected animals compared to controls. Zygote microinjection of total small RNA from sperm of infected mice partially recapitulates the behavioral phenotype of naturally born offspring, suggesting an epigenetic mechanism of behavioral inheritance in the first generation. Our results demonstrate that sperm epigenetic factors can contribute to intergenerational inheritance of behavioral changes after pathogenic infection, which could have major public health implications. : Tyebji et al. provide evidence that paternal pathogenic infection has transgenerational impacts on offspring phenotypes. They discover that Toxoplasma gondii infection induces epigenetic changes, involving small RNAs, in mouse sperm and demonstrate a mechanism involving these non-coding RNAs. This mechanism mediates transgenerational inheritance modulating offspring phenotype, including behavior. Keywords: Toxoplasma gondii, epigenetics, small RNA, transgenerational, cognitive changes

Objective: Sexually transmitted diseases (STDs), mainly lymphogranuloma venereum (LGV), induce colorectal symptoms that may be misdiagnosed as inflammatory bowel disease (IBD). This study describes patients who presented with STDs masquerading as IBD in order to improve understanding of missed diagnosis of colorectal STDs and their association with LGV in Israel. Methods: This retrospective, descriptive study characterized the clinical, endoscopic, and pathological findings of 16 patients who were diagnosed with a colorectal STD after erroneously being diagnosed with IBD. Molecular genotyping was used to characterize some of the Chlamydia trachomatis isolates. Results: All patients were men who have sex with men (MSM), mostly HIV-1-positive, and had clinical and endoscopic findings compatible with IBD. The STD was diagnosed 1–36 months after the initial diagnosis: 14 were positive for Chlamydia trachomatis, of which three were of the LGV2b (ST58) serotype and one was ST 108 serotype. Five were positive for gonorrhea and four were positive for syphilis. Several pathogens were diagnosed in six episodes. Conclusions: Colorectal STDs may resemble IBD and therefore their diagnosis may be delayed. IBD symptoms in MSM who engage in non-protected anal sex should prompt at least syphilis and anal PCR for STD testing. If C. trachomatis is diagnosed but LGV subtyping cannot be done, doxycycline 100 mg twice daily for 21 days should be recommended. Keywords: Chlamydia infection, Lymphogranuloma venereum, Neisseria gonorrhoeae, Syphilis, Proctitis, Men who have sex with men

Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippocampus of mouse models and patients and contributes to hippocampal-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling. In contrast, PKA signaling was not altered in the hippocampus of HdhQ7/Q111 mice, a full-length HD model. In line with these findings, chronic (but not acute) combined treatment with D1R plus A2AR antagonists (SCH23390 and SCH58261, respectively) normalizes PKA activity in the hippocampus, facilitates long-term potentiation in behaving R6/1 mice, and ameliorates cognitive dysfunction. By contrast, chronic treatment with either D1R or A2AR antagonist alone does not modify PKA activity or improve cognitive dysfunction in R6/1 mice. Hyperactivation of both D1R and A2AR occurs in HD striatum and chronic treatment with D1R plus A2AR antagonists normalizes striatal PKA activity but it does not affect motor dysfunction in R6/1 mice. In conclusion, we show that parallel alterations in dopaminergic and adenosinergic signaling in the hippocampus contribute to increase PKA activity, which in turn selectively participates in hippocampal-dependent learning and memory deficits in HD. In addition, our results point to the chronic inhibition of both D1R and A2AR as a novel therapeutic strategy to manage early cognitive impairment in this neurodegenerative disease.

Abstract: Although chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, 9 of whom successfully received CAR19-22 followed by NKTR-255. There were no dose-limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with 8 of 9 patients (89%) achieving measurable residual disease-negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T cells in the blood and 10-fold increases in cerebrospinal fluid CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible, and associated with high rates of durable responses. This trial was registered at www.clinicaltrials.gov as #NCT03233854., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade after the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for patients with R/R cHL who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011 to 2020 (N = 183) compared with those from 2001 to 2010 (N = 159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era with a trend toward lower nonrelapse mortality beyond 2 years after transplant. Among patients who progressed after AHCT, 4-year postprogression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients that underwent transplant in the modern era, age ≥45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, whereas receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS. Extranodal disease at relapse was associated with inferior OS. Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting., (© 2023 by The American Society of Hematology.)

The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890., (© 2021 by The American Society of Hematology.)

In the present research, a nanoaptasensor is proposed for electrochemical measurement of chloramphenicol (CAP). To this purpose, the nanocomposite prepared from graphene oxide and functionalized with (3-Aminopropyl) triethoxysilane/silver nanoparticles to the abbreviated AgNPs/[NH 2 -Si]-f-GO, was utilized to modify the glassy carbon electrode (GCE). Furthermore, the modified electrode was also investigated using the electrochemical methods such as electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The AgNPs/[NH 2 -Si]-f-GO nanocomposite was investigated by UV-Vis spectrophotometry. Fourier transform infrared (FT-IR) spectrometry and transmission electron microscopy (TEM). Moreover, [Fe(CN) 6 ] 3-/4 solution in the role of an electrochemical probe was applied. The AgNPs/[NH 2 -Si]-f-GO nanocomposite was confirmed as a good layer to covalent immobilization of aptamer (Apt) onto the GCE surface. In this sense, the DPV was used as a sensitive electrochemical technique for the measurement of CAP with an appropriate linear concentration range which was found to be between 10 pM and 0.2 μM and, with a low limit of detection, it equaled 3.3 pM. CAP which was identified in the presence of other usual antibiotics existed in the real samples., (Copyright © 2019 Elsevier B.V. All rights reserved.)