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Background/aim: Vancomycin-resistant Enterococcus causes significant morbidity, mortality, and excess healthcare costs when compared to vancomycin-susceptible isolates. Patients with hematological malignancies, especially those who undergo hematopoietic stem cell transplantation, are at a particularly high risk for infections with vancomycin-resistant Enterococcus, with mortality ranging from 40-100%. Linezolid and daptomycin are the two most commonly used antibiotics for treatment of vancomycin-resistant enterococcal infections, however, there has been recent emergence of resistance to these drugs as well., Case Report: We report the case of a 48-year-old male with hematological malignancy and graft failure post hematopoietic stem cell transplantation complicated by dialysis-dependent acute kidney injury and recurrent neutropenic fevers due to vancomycin-resistant Enterococcus faecium (VREf) bacteremia. Despite central line changes, and strict aseptic precautions, the bacteremia returned, showing resistance to daptomycin and linezolid after the second recurrence. As a final effort, using limited clinical data and in vitro studies, we utilized oritavancin off-label as salvage therapy for refractory VREf bacteremia, with subsequent clearance of blood cultures., Conclusion: This is a rare case of successful off-label use of oritavancin for recurrent multidrug-resistant VREf bacteremia in a patient with hematological malignancy after undergoing hematopoietic stem cell transplantation. It is important to increase awareness of the potential use of this novel antibiotic with increasing resistance of VREf to first-line agents., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Perceptual segregation of complex sounds such as speech and music simultaneously emanating from multiple sources is a remarkable ability that is common in humans and other animals alike. Unlike animal physiological experiments with simplified sounds or human investigations with spatially broad imaging techniques, this study combines insights from animal single-unit recordings with segregation of speech-like sound mixtures. Ferrets are trained to attend to a female voice and detect a target word, both in presence and absence of a concurrent equally salient male voice. Recordings are made in primary and secondary auditory cortical fields, and in frontal cortex. During task performance, representation of the female words becomes enhanced relative to the male in all, but especially in higher cortical regions. Analysis of the temporal and spectral response characteristics during task performance reveals how speech segregation gradually emerges in the auditory cortex. A computational model evaluated on the same voice mixtures replicates and extends these results to different attentional targets (attention to female or male voices). These findings underscore the role of the principle of temporal coherence whereby attention to a target voice binds together all neural responses coherently modulated with the target, thus ultimately forming and extracting a common auditory stream., (© 2024. The Author(s).)

Tumor-infiltrating B cells play a significant role in tumor development, progression, and prognosis, yet a comprehensive classification system is lacking. To address this gap, we present a pan-cancer single-cell RNA sequencing (scRNA-seq) atlas of tumor-infiltrating B and plasma cells across a large sample cohort. We identify key B cell subset signatures, revealing distinct subpopulations and highlighting the heterogeneity and functional diversity of these cells in the tumor microenvironment. We explore associations between B cell subsets and checkpoint inhibitor therapy responses, finding subset-specific effects on overall response. Additionally, we examine B and T cell crosstalk, identifying unique ligand-receptor pairs for specific B cell subsets, spatially validated. This comprehensive dataset serves as a valuable resource, providing a detailed atlas that enhances the understanding of B cell complexity in tumors and opens new avenues for research and therapeutic strategies., Competing Interests: Declaration of interests K.L. has the following disclosures (unrelated to this work): patent on indel burden and CPI response pending, patent on ctDNA minimal residual disease calling methods; speaker fees from Roche Tissue Diagnostics and Ellipses Pharma; research funding from CRUK TDL/Ono/LifeArc alliance and Genesis Therapeutics; and consulting roles with Monopteros Therapeutics, Kynos Therapeutics, SAGA Diagnostics, and Tempus Labs, Inc. Also unrelated to this work, K.L. is currently employed by Isomorphic Labs. J.L.R. has the following disclosures (unrelated to this work): patents filed for cancer early detection and consulting role for Achilles Therapeutics plc., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: Research studies typically quantify acute respiratory exacerbation episodes (AECOPD) among people with chronic obstructive pulmonary disease (COPD) based on self-report elicited by survey questionnaire. However, AECOPD quantification by self-report could be inaccurate, potentially rendering it an imprecise tool for identification of those with exacerbation tendency., Objective: Determine the agreement between self-reported and health records-documented quantification of AECOPD and their association with airway inflammation., Methods: We administered a questionnaire to elicit the incidence and severity of respiratory exacerbations in the three years preceding the survey among current or former heavy smokers with or without diagnosis of COPD. We then examined electronic health records (EHR) of those with COPD and those without (tobacco-exposed persons with preserved spirometry or TEPS) to determine whether the documentation of the three-year incidence of moderate to very severe respiratory exacerbations was consistent with self-report using Kappa Interrater statistic. A subgroup of participants also underwent bronchoalveolar lavage (BAL) to quantify their airway inflammatory cells. We further used multivariable regressions analysis to estimate the association between respiratory exacerbations and BAL inflammatory cell composition with adjustment for covariates including age, sex, height, weight, smoking status (current versus former) and burden (pack-years)., Results: Overall, a total of 511 participants completed the questionnaire, from whom 487 had EHR available for review. Among the 222 participants with COPD (70 ± 7 years-old; 96% male; 70 ± 38 pack-years smoking; 42% current smoking), 57 (26%) reported having any moderate to very severe AECOPD (m/s-AECOPD) while 66 (30%) had EHR documentation of m/s-AECOPD. However, 42% of those with EHR-identified m/s-AECOPD had none by self-report, and 33% of those who reported m/s-AECOPD had none by EHR, suggesting only moderate agreement (Cohen's Kappa = 0.47 ± 0.07; P < 0.001). Nevertheless, self-reported and EHR-identified m/s-AECOPD events were both associated with higher BAL neutrophils (ß ± SEM: 3.0 ± 1.1 and 1.3 ± 0.5 per 10% neutrophil increase; P ≤ 0.018) and lymphocytes (0.9 ± 0.4 and 0.7 ± 0.3 per 10% lymphocyte increase; P ≤ 0.041). Exacerbation by either measure combined was associated with a larger estimated effect (3.7 ± 1.2 and 1.0 ± 0.5 per 10% increase in neutrophils and lymphocytes, respectively) but was not statistically significantly different compared to the self-report only approach. Among the 184 TEPS participants, there were fewer moderate to very severe respiratory exacerbations by self-report (n = 15 or 8%) or EHR-documentation (n = 9 or 5%), but a similar level of agreement as those with COPD was observed (Cohen's Kappa = 0.38 ± 0.07; P < 0.001)., Discussion: While there is modest agreement between self-reported and EHR-identified m/s-AECOPD, events are missed by relying on either method alone. However, m/s-AECOPD quantified by self-report or health records is associated with BAL neutrophilia and lymphocytosis., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Guidelines recommend that patients with acute venous thromboembolism (VTE) represented by low-risk deep vein thrombosis (DVT) and pulmonary embolism (PE) receive initial treatment at home versus at the hospital, but a large percentage of these patients are not managed at home. This study assessed the effectiveness of a quality intervention on provider knowledge and confidence in evaluating outpatient treatment for patients with VTE in the emergency department (ED)., Methods: A pilot program to overcome obstacles to outpatient VTE treatment in appropriate patients was initiated at Baylor Scott & White Health Temple ED. Subsequently, a formalized quality intervention with a targeted educational program was developed and delivered to ED providers. Provider surveys were administered pre- and post-quality intervention in order to assess clinical knowledge, confidence levels, and perceived barriers. Patient discharge information was extracted from electronic health records., Results: Twenty-five ED providers completed the pre- and post-surveys; 690 and 356 patients with VTE were included in the pre- and post-pilot and pre- and post-quality intervention periods, respectively. Many ED providers reported that a major barrier to discharging patients to outpatient care was the lack of available and adequate patient follow-up appointments. Notably, after the quality intervention, an increase in provider clinical knowledge and confidence scores was observed. Discharge rates for patients with VTE increased from 25.6% to 27.5% after the pilot intervention and increased from 28.5% to 29.9% after the quality intervention, but these differences were not statistically significant. Despite instantaneous uptick in discharge rates after the interventions, there was not a long-lasting effect., Conclusion: Although the quality intervention led to improvements in provider clinical knowledge and confidence and identified barriers to discharging patients with VTE, discharge rates remained stable, underscoring the need for additional endeavors., (© 2024. The Author(s).)

The paradigm for macrophage characterization has evolved from the simple M1/M2 dichotomy to a more complex model that encompasses the broad spectrum of macrophage phenotypic diversity, due to differences in ontogeny and/or local stimuli. We currently lack an in-depth pan-cancer single cell RNA-seq (scRNAseq) atlas of tumour-associated macrophages (TAMs) that fully captures this complexity. In addition, an increased understanding of macrophage diversity could help to explain the variable responses of cancer patients to immunotherapy. Our atlas includes well established macrophage subsets as well as a number of additional ones. We associate macrophage composition with tumour phenotype and show macrophage subsets can vary between primary and metastatic tumours growing in sites like the liver. We also examine macrophage-T cell functional cross talk and identify two subsets of TAMs associated with T cell activation. Analysis of TAM signatures in a large cohort of immune checkpoint inhibitor-treated patients (CPI1000 + ) identify multiple TAM subsets associated with response, including the presence of a subset of TAMs that upregulate collagen-related genes. Finally, we demonstrate the utility of our data as a resource and reference atlas for mapping of novel macrophage datasets using projection. Overall, these advances represent an important step in both macrophage classification and overcoming resistance to immunotherapies in cancer., (© 2024. The Author(s).)

Introduction: Budd-Chiari syndrome (BCS) is primarily a disease of hepatic vein blockage, which involves a backflow of blood to the liver. Although there have been many causes linked to this disease, most commonly, it occurs due to hypercoagulable states and blood disorders. In recent times, there has been a fast spread of knowledge regarding early diagnosis and various treatment modalities, which has enabled the prevention of mortality in most cases. This has primarily spread through research articles published in various journals. Thus, the article aims to compare the gender trend ratios to identify the associated discrepancies in terms of male and female author contributions who have been the primary authors for articles pertaining to this disease.  Methodology: A PubMed database between the years 2013 and 2022 was used for the bibliometric analysis. The gender of the primary author was analyzed by NamSor, an application programming interface (API). The statistical analysis was conducted using R software, the ARIMA model, and graphs were prepared using Datawrapper., Results: Out of 667 articles extracted, the analysis showed that there were 455 (68.2%) first male authors and 212 (31.8%) first female authors. We also formulated various other results, which depicted a higher female-to-male author ratio including various journals and different countries. Although there has been an increasing trend of male authors as compared to female authors, this study found that male authorship for research on this disease is still higher., Conclusions: This study depicts that there is a necessity to draw attention to the inequitable systems favoring men over women for publications. The predictive analysis conducted also helps to foresee the trend in the next few years and explains the necessity of addressing the disparities among both genders in healthcare systems., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Samuel B et al.)

Segregation of complex sounds such as speech, music and animal vocalizations as they simultaneously emanate from multiple sources (referred to as the "cocktail party problem") is a remarkable ability that is common in humans and animals alike. The neural underpinnings of this process have been extensively studied behaviorally and physiologically in non-human animals primarily with simplified sounds (tones and noise sequences). In humans, segregation experiments utilizing more complex speech mixtures are common; but physiological experiments have relied on EEG/MEG/ECoG recordings that sample activity from thousands of neurons, often obscuring the detailed processes that give rise to the observed segregation. The present study combines the insights from animal single-unit physiology with segregation of speech-like mixtures. Ferrets were trained to attend to a female voice and detect a target word, both in presence or absence of a concurrent, equally salient male voice. Single neuron recordings were obtained from primary and secondary ferret auditory cortical fields, as well as frontal cortex. During task performance, representation of the female words became more enhanced relative to those of the (distractor) male in all cortical regions, especially in the higher auditory cortical field. Analysis of the temporal and spectral response characteristics during task performance reveals how speech segregation gradually emerges in the auditory cortex. A computational model evaluated on the same voice mixtures replicates and extends these results to different attentional targets (attention to female or male voices). These findings are consistent with the temporal coherence theory whereby attention to a target voice anchors neural activity in cortical networks hence binding together channels that are coherently temporally-modulated with the target, and ultimately forming a common auditory stream., Competing Interests: Competing Interests The authors have declared no competing interest.

Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of antigen-specific PC precursors remain to be elucidated. Here, using a model antigen in mice, we demonstrate biphasic generation of PC precursors, with those generating long-lived bone marrow PCs preferentially produced in the late phase of GC response. Clonal tracing using single-cell RNA sequencing and B cell antigen receptor sequencing in spleen and bone marrow compartments, coupled with adoptive transfer experiments, reveals a new PC transition state that gives rise to functionally competent PC precursors. The latter undergo clonal expansion, dependent on inducible expression of TIGIT. We propose a model for the proliferation and programming of precursors of long-lived PCs, based on extended antigen encounters in the GC., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Non-Hispanic Black breast cancer survivors have poorer outcomes and higher mortality rates than White survivors, but systemic biological mechanisms underlying these disparities are unclear. We used circulating leukocytes as a surrogate for measuring systemic mechanisms, which might be different from processes in the target tissue (e.g., breast). We investigated race-based differences in DNA damage and repair, using a novel CometChip assay, in circulating leukocytes from breast cancer survivors who had completed primary cancer therapy and were cancer free. We observed novel race-based differences in systemic DNA damage and repair activity in cancer survivors, but not in cells from healthy volunteers. Basal DNA damage in leukocytes was higher in White survivors, but Black survivors showed a much higher induction after bleomycin treatment. Double-strand break repair activity was also significantly different between the races, with cells from White survivors showing more sustained repair activity compared to Black leukocytes. These results suggest that cancer and cancer therapy might have long-lasting effects on systemic DNA damage and repair mechanisms that differ in White survivors and Black survivors. Findings from our preliminary study in non-cancer cells (circulating leukocytes) suggest systemic effects beyond the target site, with implications for accelerated aging-related cancer survivorship disparities.

Medical affairs professionals are pivotal players at the intersection of medical innovation and practice in the pharmaceutical industry. They are uniquely positioned to translate complex medical knowledge into actionable insights for internal and external stakeholders. Industry-led continuing medical education (CME) programs, guided by these professionals, hold the potential to markedly improve clinicians' application of evidence-based medicine (EBM) in clinical settings, thereby elevating patient care outcomes. However, current CME techniques often overlook the integration of diverse disciplines such as educational theories, cognitive psychology, information mastery, and implementation science, which are important for effective real-time decision-making in patient care. This gap in integrating implementation science is vital, as it is key in ensuring that medical innovations are not just developed but also effectively implemented and efficiently utilized in clinical settings. In this opinion article, we aim to highlight the crucial yet often underrecognized role of medical affairs professionals in shaping robust and practical CME programs within the industry. We explore emerging trends and approaches in medical education and CME based on the principles of adult education. Additionally, we explore how medical affairs professionals can effectively drive the adoption of EBM in clinical practice. This exploration aims to provide insights into enhancing CME programs, with medical affairs professionals at the forefront of innovation and leadership in bridging gaps in clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Context: Peripheral neuropathy (PN) is a multifaceted complication characterized by nerve damage due to oxidative stress, inflammatory mediators, and dysregulated metabolic processes. Early PN manifests as sensory changes that develop progressively in a "stocking and glove" pattern., Methods and Mechanisms: A thorough review of literature has been done to find the molecular pathology, clinical trials that have been conducted to screen the effects of different drugs, current treatments and novel approaches used in PN therapy. Diabetic neuropathy occurs due to altered protein kinase C activity, elevated polyol pathway activity in neurons, and Schwann cells-induced hyperglycemia. Other causes involve chemotherapy exposure, autoimmune ailments, and chronic ethanol intake., Conclusion: Symptomatic treatments for neuropathic pain include use of tricyclic antidepressants, anticonvulsants, and acetyl-L-carnitine. Patients will have new hope if clinicians focus on novel therapies including gene therapy, neuromodulation techniques, and cannabidiol as an alternative to traditional medications, as management is still not ideal.

Analysis of the human hematopoietic progenitor compartment is being transformed by single-cell multimodal approaches. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) enables coupled surface protein and transcriptome profiling, thereby revealing genomic programs underlying progenitor states. To perform CITE-seq systematically on primary human bone marrow cells, we used titrations with 266 CITE-seq antibodies (antibody-derived tags) and machine learning to optimize a panel of 132 antibodies. Multimodal analysis resolved >80 stem, progenitor, immune, stromal and transitional cells defined by distinctive surface markers and transcriptomes. This dataset enables flow cytometry solutions for in silico-predicted cell states and identifies dozens of cell surface markers consistently detected across donors spanning race and sex. Finally, aligning annotations from this atlas, we nominate normal marrow equivalents for acute myeloid leukemia stem cell populations that differ in clinical response. This atlas serves as an advanced digital resource for hematopoietic progenitor analyses in human health and disease., (© 2024. The Author(s).)

Background and Aims: LMA ProSeal (PLMA) is a commonly used airway maintenance device in elective procedures and is routinely inserted from the head-end of the patient. It is also used in pre-hospital emergencies where it may not always be possible to access the head-end. This study aims to compare the insertion characteristics of PLMA when inserted while standing, either at the head-end or from the front., Material and Methods: After institutional ethics committee approval, 60 consenting patients of either sex, between 18 and 60 years, ASA class I/II, and scheduled to undergo elective surgeries were randomly allocated to either group H (head-end insertion) or group F (front-end insertion). Patients with anticipated difficult airway, chronic respiratory disease, obesity, and who were pregnant were excluded. Insertion time, ease of insertion, fiber optic view, ease of drain tube insertion, number of attempts and success rate were noted. Normally distributed quantitative variables were compared using t -test, and qualitative variables were compared using Chi-squared test. A P < 0.05 was considered significant., Results: Insertion time in group H (23.76 ± 4.48 s) was lesser than in group F (30.53 ± 6.23s) ( P = 0.027). Ease of insertion ( P = 0.052), fiber optic view, ease of drain tube placement ( P = 1.000), and number of attempts ( P = 1.000) were comparable among the groups., Conclusion: Although the insertion time from the front is longer than from the head-end, the other insertion characteristics of PLMA including ease of its insertion, placement and success rate of placement are similar when it is inserted from the front or from the head-end. It is an appropriate airway device for securing the airway when the head-end is inaccessible., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Anaesthesiology Clinical Pharmacology.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 has been a dynamically changing virus, requiring the development of adapted vaccines. This study estimated the potential public health impact alternative vaccination strategies for COVID-19 in Singapore., Research Design and Methods: The outcomes of alternative vaccination strategies with a future adapted vaccine were estimated using a combined Markov decision tree model. The population was stratified by high- and standard-risk. Using age-specific inputs informed by local surveillance data and published sources, the model estimated health (case numbers, hospitalizations, and deaths) and economic (medical costs and productivity losses) outcomes in different age and risk subpopulations., Results: Booster vaccination in only the elderly and high-risk subpopulation was estimated to avert 278,614 cases 21,558 hospitalizations, 239 deaths, Singapore dollars (SGD) 277 million in direct medical costs, and SGD 684 million in indirect medical costs. These benefits increased as vaccination was expanded to other subpopulations. Increasing the booster vaccination coverage to 75% of the standard-risk population averted more deaths (3%), hospitalizations (29%), infections (145%), direct costs (90%), and indirect costs (192%) compared to the base case., Conclusions: Broader vaccination strategies using an adapted booster vaccine could have substantial public health and economic impact in Singapore.

The dynamics of the hematopoietic flux responsible for blood cell production in native conditions remains a matter of debate. Using CITE-seq analyses, we uncovered a distinct progenitor population that displays a cell cycle gene signature similar to the one found in quiescent hematopoietic stem cells. We further determined that the CD62L marker can be used to phenotypically enrich this population in the Flt3+ multipotent progenitor (MPP4) compartment. Functional in vitro and in vivo analyses validated the heterogeneity of the MPP4 compartment and established the quiescent/slow-cycling properties of the CD62L- MPP4 cells. Furthermore, studies under native conditions revealed a novel hierarchical organization of the MPP compartments in which quiescent/slow-cycling MPP4 cells sustain a prolonged hematopoietic activity at steady-state while giving rise to other lineage-biased MPP populations. Altogether, our data characterize a durable and productive quiescent/slow-cycling hematopoietic intermediary within the MPP4 compartment and highlight early paths of progenitor differentiation during unperturbed hematopoiesis., (© 2023 Solomon et al.)

CO 2 , a byproduct from various industrial reactions, must not be released into the atmosphere and should be managed through capture, conversion, and utilization. The first step in converting CO 2 into valuable products is to break the C-O bond. This work focuses on designing Single Atom Catalysts (SACs) by doping Cu(211) surface with 13 different s, p, and d block elements with an aim to minimize the activation barrier for C-O bond cleavage. Our work demonstrates that SACs of Mg/Al/Pt@Cu(211) favor CO 2 chemisorption compared to Cu(211) where CO 2 physisorbs. The barrier for CO 2 dissociation is lowest for Mg@Cu(211) and it increases in the order Mg@Cu(211) < Al@Cu(211) < Pt@Cu(211) < Zn@Cu(211) < Ga@Cu(211) < Cu@Cu(211) < Pd@Cu(211). These findings suggest that doping Cu(211) with earth-abundant metal like Mg can potentially be a viable catalyst for CO 2 conversion, providing a promising solution to reduce carbon footprint and mitigate climate change., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications.

Background: Checkpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor transcriptomic changes induced by CPI may improve our understanding of the mechanisms of sensitivity and resistance., Methods: We assembled a cohort of longitudinal pre-therapy and on-therapy samples from 174 patients treated with CPI across six cancer types by leveraging transcriptomic sequencing data from five studies., Results: Meta-analyses of published RNA markers revealed an on-therapy pattern of immune reinvigoration in patients with breast cancer, which was not discernible pre-therapy, providing biological insight into the impact of CPI on the breast cancer immune microenvironment. We identified 98 breast cancer-specific correlates of CPI response, including 13 genes which are known IO targets, such as toll-like receptors TLR1 , TLR4 , and TLR8 , that could hold potential as combination targets for patients with breast cancer receiving CPI treatment. Furthermore, we demonstrate that a subset of response genes identified in breast cancer are already highly expressed pre-therapy in melanoma, and additionally we establish divergent RNA dynamics between breast cancer and melanoma following CPI treatment, which may suggest distinct immune microenvironments between the two cancer types., Conclusions: Overall, delineating longitudinal RNA dynamics following CPI therapy sheds light on the mechanisms underlying diverging response trajectories, and identifies putative targets for combination therapy., Competing Interests: Competing interests: DB reports personal fees from NanoString and AstraZeneca, and has a patent PCT/GB2020/050221 issued on methods for cancer prognostication. KD provides consultancy services to Achilles Therapeutics. YW consults for PersonGen Biotherapeutics and E15 VC. MK received research funding paid to the institute from BMS, Roche, AstraZeneca, has advisory roles compensated to the institute for: Daiichi Sankyo, BMS, MSD, Novartis, Roche outside the submitted work, and speakers’ fee paid to the institute from: Roche, BMS and Gilead. CS acknowledges grant support from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc—collaboration in minimal residual disease sequencing technologies) and Ono Pharmaceutical. CS is an AstraZeneca Advisory Board member and chief investigator for the AZ MeRmaiD 1 and 2 clinical trials, and is also co-chief investigator of the NHS Galleri trial, funded by GRAIL, and a paid member of GRAIL’s Scientific Advisory Board. He receives consultant fees from Achilles Therapeutics (where he is also a Scientific Advisory Board member), Bicycle Therapeutics (where he is also a Scientific Advisory Board member), Genentech, Medicxi, Roche Innovation Centre—Shanghai, Metabomed (until July 2022) and the Sarah Cannon Research Institute, had stock options in Apogen Biotechnologies and GRAIL until June 2021, currently has stock options in Epic Bioscience and Bicycle Therapeutics, and has stock options in and is co-founder of Achilles Therapeutics. CS is an inventor on a European patent application relating to assay technology to detect tumor recurrence (PCT/GB2017/053289); the patent has been licensed to commercial entities and under his terms of employment CS is due a revenue share of any revenue generated from such license(s). CS holds patents relating to targeting neoantigens (PCT/EP2016/059401), identifying clinical response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA loss of heterozygosity (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients whose cancer responds to treatment (PCT/GB2018/051912), detecting tumor mutations (PCT/US2017/28013), methods for lung cancer detection (US20190106751A1), and identifying insertion/deletion mutation targets (European and US, PCT/GB2018/051892), and is co-inventor to a patent application to determine methods and systems for tumor monitoring (PCT/EP2022/077987). CS is a named inventor on a provisional patent protection related to a ctDNA detection algorithm., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Methicillin-resistant Staphylococcus aureus (MRSA) is a common hospital-acquired pathogen and can cause a wide spectrum of infections. In recent years, MRSA has emerged as a significant public health concern, particularly in hospitals. Intensive care units (ICUs) and burn units are high-risk areas for hospital-acquired MRSA infections, which can lead to increased morbidity, mortality, and healthcare costs. MRSA exhibits resistance to multiple antibiotics and can cause serious infections, including but not limited to pneumonia, endocarditis, and cutaneous infections, particularly in patients with burn injuries. The prevention and effective management of MRSA infections in both burn patients and those in ICUs is crucial, with strategies like isolation, regular disinfection, and prophylactic intranasal mupirocin. Early diagnosis of MRSA infection and isolation of patients is vital to prevent the spread of MRSA. Implementation of prevention strategies faces many challenges, such as cost, and the most successful infection management practices are still debated. This review has highlighted the substantial concern of MRSA colonization in intensive care and burn units. MRSA poses a significant risk to vulnerable patients, influenced by factors such as compromised immunity and invasive procedures. The prevalence of MRSA colonization varies, influenced by regional factors and infection control practices. Combating MRSA requires a multifaceted approach, including stringent infection control measures and education for healthcare workers and patients. As we move forward, continued research and cooperation are essential to reduce the burden of MRSA in these critical care settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Samuel et al.)

Competing Interests: There are no conflicts of interest.

Introduction: Epidemiological modeling is widely used to offer insights into the COVID-19 pandemic situation in Asia. We reviewed published computational (mathematical/simulation) models conducted in Asia that assessed impacts of pharmacological and non-pharmacological interventions against COVID-19 and their implications for vaccination strategy., Methods: A search of the PubMed database for peer-reviewed, published, and accessible articles in English was performed up to November 2022 to capture studies in Asian populations based on computational modeling of outcomes in the COVID-19 pandemic. Extracted data included model type (mechanistic compartmental/agent-based, statistical, both), intervention type (pharmacological, non-pharmacological), and procedures for parameterizing age. Findings are summarized with descriptive statistics and discussed in terms of the evolving COVID-19 situation., Results: The literature search identified 378 results, of which 59 met criteria for data extraction. China, Japan, and South Korea accounted for approximately half of studies, with fewer from South and South-East Asia. Mechanistic models were most common, either compartmental (61.0%), agent-based (1.7%), or combination (18.6%) models. Statistical modeling was applied less frequently (11.9%). Pharmacological interventions were examined in 59.3% of studies, and most considered vaccination, except one study of an antiviral treatment. Non-pharmacological interventions were also considered in 84.7% of studies. Infection, hospitalization, and mortality were outcomes in 91.5%, 30.5%, and 30.5% of studies, respectively. Approximately a third of studies accounted for age, including 10 that also examined mortality. Four of these studies emphasized benefits in terms of mortality from prioritizing older adults for vaccination under conditions of a limited supply; however, one study noted potential benefits to infection rates from early vaccination of younger adults. Few studies (5.1%) considered the impact of vaccination among children., Conclusion: Early in the COVID-19 pandemic, non-pharmacological interventions helped to mitigate the health burden of COVID-19; however, modeling indicates that high population coverage of effective vaccines will complement and reduce reliance on such interventions. Thus, increasing and maintaining immunity levels in populations through regular booster shots, particularly among at-risk and vulnerable groups, including older adults, might help to protect public health. Future modeling efforts should consider new vaccines and alternative therapies alongside an evolving virus in populations with varied vaccination histories., Competing Interests: MK, CM, EO, JS, KT, and JY were employed by Pfizer Inc. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Thakkar, Spinardi, Yang, Kyaw, Ozbilgili, Mendoza and Oh.)

How two-chambered hearts in basal vertebrates have evolved from single-chamber hearts found in ancestral chordates remains unclear. Here, we show that the teleost sinus venosus (SV) is a chamber-like vessel comprised of an outer layer of smooth muscle cells. We find that in adult zebrafish nr2f1a mutants, which lack atria, the SV comes to physically resemble the thicker bulbus arteriosus (BA) at the arterial pole of the heart through an adaptive, hypertensive response involving smooth muscle proliferation due to aberrant hemodynamic flow. Single cell transcriptomics show that smooth muscle and endothelial cell populations within the adapting SV also take on arterial signatures. Bulk transcriptomics of the blood sinuses flanking the tunicate heart reinforce a model of greater equivalency in ancestral chordate BA and SV precursors. Our data simultaneously reveal that secondary complications from congenital heart defects can develop in adult zebrafish similar to those in humans and that the foundation of equivalency between flanking auxiliary vessels may remain latent within basal vertebrate hearts., (© 2023. Springer Nature Limited.)

Objective: Labor analgesia can be maintained with a continuous epidural infusion, supplemented by patient-controlled epidural boluses. patient-controlled epidural boluses use and timing require numeric understanding, as patients need to understand when they can administer supplemental boluses, lockout intervals, and total doses. We hypothesized that women with lower numeric literacy have a higher rate of provider-administered supplemental boluses for breakthrough pain because they do not understand the concept behind patient-controlled epidural boluses., Design: Pilot observational study SETTING: Labor and Delivery Suite PARTICIPANTS: Nulliparous, English-speaking patients with singleton, vertex pregnancies admitted for postdates (gestational age ≥ 41 weeks) induction of labor requesting neuraxial labor analgesia., Interventions: Combined spinal-epidural labor analgesia was initiated with intrathecal fentanyl and epidural analgesia was maintained using continuous epidural infusion with patient-controlled epidural boluses., Measurements and Findings: Numeric literacy was assessed using the Lipkus 7-item expanded numeracy test. Patients were stratified by whether or not they required supplemental provider-administered analgesia and patient-controlled epidural boluses use patterns were evaluated. A total of 89 patients completed the study. There were no demographic differences between patients who required supplemental analgesia compared with those who did not. Patients that required supplemental analgesia were more likely to request and receive patient-controlled epidural boluses (P<0.001). Hourly bupivacaine requirement was higher in women with breakthrough pain. There were no differences in numeric literacy between the two groups., Key Conclusions: Patients who required treatment of breakthrough pain had higher patient-controlled epidural boluses demands-to-delivery ratio. Numeric literacy was not correlated with the need for provider-administered supplemental boluses., Implications for Practice: Easy to understand scripts on how to use patient-controlled epidural boluses allows for understanding of patient-controlled epidural boluses use., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Pediatric oncology, which includes cancer screening and therapy in children, poses significant challenges in low- and middle-income countries (LMICs). Palliative care improves children's and their families' quality of life. In LMICs, palliative care resources are scarce, resulting in poor symptom management, psychological support, and spiritual care. All relevant English-language articles on pediatric palliative oncology were searched in PubMed, Google Scholar, Scopus, and Medline databases using the following keywords: "Pediatric Oncology," "Pediatric Palliative Oncology," "Pediatric Palliative Care," "Palliative Care," "Child Cancer," and "Lower- and Middle-Income Countries." This study highlights the significance of incorporating palliative care early in therapy and the recommendations may improve the competence of information provided by medical professionals to patients and families. LMICs have the potential to improve overall treatment and outcomes for child cancer patients and their families by prioritizing the integration of palliative care, guaranteeing a compassionate and dignified attitude toward the disease., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Posterior cervical foraminotomy (PCF) and anterior cervical discectomy and fusion (ACDF) are 2 commonly used surgical approaches to address cervical radiculopathy. Demonstrating superiority in clinical outcomes and durability of one of the approaches could change clinical practice on a large scale. This is the largest reported single-institutional retrospective cohort of single-level PCFs compared with single-level ACDFs for cervical radiculopathy., Methods: Patients undergoing either ACDF or PCF between 2014 and 2021 were identified using Current Procedural Terminology codes. Medical records were reviewed for demographics, surgical characteristics, and reoperations. Statistical analysis included t tests for continuous characteristics and c 2 testing for categorical characteristics., Results: In total, 236 single-level ACDFs and 138 single-level PCFs were included. There was no significant difference in age (51.0 vs 51.3 years), body mass index (BMI; 28.6 vs 28.1), or Charlson Comorbidity Index (1.89 vs 1.68) between patients who underwent ACDF and those who underwent PCF. There was no difference in the rate of reoperation (5.1% vs 5.1%), time to reoperation (247 vs 319 days), or reoperation for recurrent symptoms (1.7% vs 2.9%) for ACDF vs PCF. Hospital length of stay (LOS) was longer for ACDF compared with PCF (1.65 vs 1.35 days, P = 0.041), and the overall readmission rate after ACDF was 20.8% vs 10.9% after PCF ( P = 0.014)., Conclusions: Overall reoperation rates or reoperation for recurrent symptoms between ACDF and PCF were not significantly different, demonstrating that either procedure effectively addresses the indication for surgery. There was a significantly longer LOS after ACDF than PCF, and readmission rates at 90 days and 1 year were higher after ACDF., Competing Interests: Declaration of Conflicting Interests : The authors report no conflicts of interest in this work., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2023 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, T STR , characterized by heat shock gene expression. T STR cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with genomic, pathological and clinical features in 375 patients from 23 cohorts, including 171 patients who received immune checkpoint blockade therapy. We also found significantly upregulated heat shock gene expression in intratumoral CD4/CD8 + cells following immune checkpoint blockade treatment, particularly in nonresponsive tumors, suggesting a potential role of T STR cells in immunotherapy resistance. Our well-annotated T cell reference maps, web portal and automatic alignment/annotation tool could provide valuable resources for T cell therapy optimization and biomarker discovery., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The rapid rollout of vaccines to combat the coronavirus disease 2019 (COVID-19) pandemic over the past 2 years has resulted in the use of various vaccine platforms and regional differences in COVID-19 vaccine implementation strategies. The aim of this narrative review was to summarize evolving COVID-19 vaccine recommendations in countries in Latin America, Asia, and Africa and the Middle East across various vaccine platforms, age groups, and specific subpopulations. Nuances in primary and booster vaccination schedules were evaluated, and the preliminary impact of such diverse vaccination strategies are discussed, including key vaccine effectiveness data in the era of Omicron-lineage variants. Primary vaccination rates for included Latin American countries were 71-94% for adults and between 41% and 98% for adolescents and children; rates for first booster in adults were 36-85%. Primary vaccination rates for adults in the included Asian countries ranged from 64% in the Philippines to 98% in Malaysia, with corresponding booster rates varying from 9% in India to 78% in Singapore; for adolescents and children, primary vaccination rates ranged from 29% in the Philippines to 93% in Malaysia. Across included African and Middle Eastern countries, primary vaccination rates in adults varied widely from 32% in South Africa to 99% in the United Arab Emirates; booster rates ranged from 5% in South Africa to 60% in Bahrain. Evidence from the regions studied indicates preference of using an mRNA vaccine as a booster on the basis of safety and effectiveness of observed real-world data, especially during circulation of Omicron lineages. Vaccination against COVID-19 remains of paramount importance to reduce the burden of disease; strategies to overcome vaccine inequity, fatigue, hesitancy, and misinformation and to ensure adequate access and supply are also important., (© 2023. Pfizer Inc.)

The Notch signaling pathway is an important therapeutic target for the treatment of inflammatory diseases and cancer. We previously created ligand-specific inhibitors of Notch signaling comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain, called Notch decoys, which bound ligands, blocked Notch signaling, and showed anti-tumor activity with low toxicity. However, the study of their function depended on virally mediated expression, which precluded dosage control and limited clinical applicability. We have refined the decoy design to create peptibody-based Notch inhibitors comprising the core binding domains, EGF-like repeats 10-14, of either Notch1 or Notch4. These Notch peptibodies showed high secretion properties and production yields that were improved by nearly 100-fold compared to previous Notch decoys. Using surface plasmon resonance spectroscopy coupled with co-immunoprecipitation assays, we observed that Notch1 and Notch4 peptibodies demonstrate strong but distinct binding properties to Notch ligands DLL4 and JAG1. Both Notch1 and Notch4 peptibodies interfere with Notch signaling in endothelial cells and reduce expression of canonical Notch targets after treatment. While prior DLL4 inhibitors cause hyper-sprouting, the Notch1 peptibody reduced angiogenesis in a 3-dimensional in vitro sprouting assay. Administration of Notch1 peptibodies to neonate mice resulted in reduced radial outgrowth of retinal vasculature, confirming anti-angiogenic properties. We conclude that purified Notch peptibodies comprising EGF-like repeats 10-14 bind to both DLL4 and JAG1 ligands and exhibit anti-angiogenic properties. Based on their secretion profile, unique Notch inhibitory activities, and anti-angiogenic properties, Notch peptibodies present new opportunities for therapeutic Notch inhibition., (© 2022. The Author(s).)

Dy 3+ -doped CaY 2 Al 4 SiO 12 phosphors were prepared using the sol-gel method. X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and energy dispersive spectroscopy analyses (EDS) were used to analyse the crystal structure, morphology, and elemental composition of the prepared samples. The luminescence behaviour of the sample was investigated using photoluminescence (PL) and thermoluminescence (TL) techniques. The prepared CaY 2 Al 4 SiO 12 :xDy 3+ phosphor showed a characteristic blue and yellow emission at ~480 and 583 nm, respectively, with an excitation wavelength of 350 nm. The most intense PL emission was found for a 4 mol% doping concentration of Dy 3+ ions. The CIE diagram of the phosphor showed bluish-white colour emission. For TL studies, the prepared phosphors were irradiated with a 60 Co γ (gamma) source and the TL glow curve of the CaY 2 Al 4 SiO 12 :0.04Dy 3+ phosphor showed three overlapped peaks. For the Gaussian peaks, Chen's peak shape method was applied to determine the kinetic parameters of the samples., (© 2023 John Wiley & Sons Ltd.)

Background: Surgical resection of posterior fossa tumors (PFT) in the pediatric age group often results in significant intraoperative blood loss. The primary objective was to assess the effect of tranexamic acid (TXA) on blood loss and transfusion requirement in pediatric patients undergoing excision of PFT., Methods: In this retrospective study, all pediatric patients ≤ 18 years, who underwent PFT resection over a period of 7 years, were included. The patient and surgical characteristics, estimated blood loss (EBL), the need for blood and blood product transfusion, use of crystalloids, vasopressors, and any adverse events like seizures and thromboembolic events were recorded and compared between Group A who received TXA and Group B who did not., Results: The study included 50 patients, out of which 36 belonged to Group A and 14 to Group B. The median age was 8 years (IQR, 2-17) and the mean BMI was 16.46 ± 4.11 kg/m 2 . The mean EBL was 224.29 ± 110.36 ml in group A (n = 36) and 362 ± 180.11 ml in group B (n = 14) (p = 0.007). The intraoperative volume of crystalloid use was significantly higher in group B (p = 0.04). The requirement of blood and blood product transfusion was similar between the groups, but the volume of blood transfusion per kg body weight was higher in group B, 8.3 (IQR, 6.7-11.1) ml/kg in Group A versus 10.5 (IQR, 8.1-16.1) ml/kg in Group B (p-value 0.3). The rates of complications noted in the form of seizures and thromboembolic events were comparable., Conclusion: The use of TXA in the pediatric population undergoing PFT resection aids in reducing blood loss during the surgery without increasing complications., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The most prevalent cause of mortality in children with hypertrophic cardiomyopathy (HCM) is sudden cardiac death (SCD), which happens more frequently than in adult patients. Risk stratification tactics have generally been drawn from adult practice, however emerging data has revealed significant disparities between children and adult cohorts, implying the need for pediatric-specific risk stratification methodologies. We conducted an all-language literature search on Medline, Cochrane, Embase, and Google Scholar until October 2021. The following search strings and Medical Subject Heading (MeSH) terms were used: "HCM," "SCD," "Sudden Cardiac Death," and "Childhood Onset HCM." We explored the literature on the risk of SCD in HCM for its epidemiology, pathophysiology, the role of various genes and their influence, associated complications leading to SCD and preventive and treatment modalities. Childhood-onset HCM is linked to significant life-long morbidity and mortality, including a higher SCD rate in children than in adults. The present focus is on symptom relief and avoiding illness-related consequences, but the prospect of future disease-modifying medicines offers an intriguing opportunity to alter disease expression and outcomes in these young individuals. Current preventive recommendations promote implantable cardioverter defibrillator placement based on cumulative risk factor thresholds, although they have been demonstrated to have weak discriminating capacity. This article addresses questions and discusses the etiology, risk factors, and method to risk stratification for SCD in children with HCM., Competing Interests: Conflicts of Interest & Source of Funding In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background Treatment of pain and inflammation form the mainstay of osteoarthritis (OA) management. Non-steroidal anti-inflammatory drugs (NSAIDs), due to their inflammation-blocking mechanism, are a highly effective class of drugs for chronic pain and inflammation in OA. However, this comes at a cost of increased risk for multiple adverse effects, including gastrointestinal bleeding, cardiovascular side effects, and NSAID-induced nephrotoxicity. To minimize the potential risk of an adverse event, numerous regulatory bodies and medical societies recommend using the lowest effective NSAID dose for the shortest time necessary. One potential strategy to achieve this is the use of disease-modifying osteoarthritis drugs (DMOADs) containing anti-inflammatory and analgesic properties instead of NSAIDs for the management of OA. This study focuses on the efficacy of Clagen™ [Aflapin ( Boswellia serrata extract) + native type 2 collagen + Mobilee (hyaluronic acid (60-70%), polysaccharides (>10%), and collagen (>5%)) + CurQlife (Curcumin)] for the symptomatic improvement in OA patients as well as if this combination is effective in the long-term management of OA instead of NSAIDs. Methodology In this retrospective observational study, a total of 300 patients were screened, of whom 100 OA patients who fulfilled the criteria and agreed to be part of the study were enrolled. The data were analyzed to evaluate the efficacy of the nutraceutical formulation Clagen™ in patients with OA of the knee. From the baseline to two months, primary outcomes of improvement in the Visual Analog Scale (VAS) score, range of motion, and Knee Injury and Osteoarthritis Outcome Score (KOOS) were measured at monthly follow-up. Statistical analyses were performed according to the results obtained from the parameters. The tests were performed at a 5% significance level (p <0.05). The qualitative characteristics were described using absolute and relative frequencies, and the quantitative measures were described as summary measures (mean, standard deviation). Results Of the 100 patients enrolled in the study, 99 (64 males and 35 females) completed the study. The mean age of the patients was 50.6 ± 13.9 years, and the mean body mass index was 24.5 ± 3.5 kg/m 2 . The statistical analysis of the outcomes from the baseline to the two-month follow-up was analyzed using paired t-test. The difference in the mean of VAS pain score at baseline and two months was 3.3 ± 1.8 [t (97) = 18.2; p < 0.05], which showed a significant reduction in pain at two months. Moreover, the difference in the mean of the goniometer value of 7.3 ± 7.3 [t (98) = -10.0, p < 0.05] indicated statistically significant improvements in the range of motion. It was also observed that Clagen™ significantly improved the composite KOOS score by 10.8% at the end of two months. Similarly, KOOS scores for Symptoms, Function, and Quality of Life showed improvements of 9.6%, 9.8%, and 7.8%, respectively, and were statistically significant (p < 0.05). Conclusions Clagen™ exerted positive adjuvant effects in the management of OA. The combination not only improved the symptoms and quality of life but, in the light of future perspective, NSAIDs can be withdrawn in OA patients, considering their long-term negative effects. To validate these findings further long-term studies with a comparison arm of NSAIDs are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Kamat et al.)

A 5-month-old healthy infant presented with acute flaccid weakness, anisocoria, and urinary retention with clinical suspicion of acute flaccid myelitis versus acute transverse myelitis.

Background: Coronavirus disease 2019 (COVID-19) case numbers have increased following the emergence of the Omicron variant. This study estimated the impact of introducing and increasing the coverage of an Omicron-adapted bivalent booster vaccine in Malaysia., Research Design and Methods: A combined cohort Markov decision tree model was used to compare booster vaccination with an Omicron-adapted bivalent COVID-19 vaccine versus no booster vaccination in Malaysia. The model utilized age-specific data from January 2021 to March 2022 derived from published sources. The outcomes of interest included case numbers, hospitalizations, deaths, medical costs, and productivity losses. The population was stratified into high-risk and standard-risk subpopulations, and the study evaluated the benefits of increased coverage in different age and risk groups., Results: Vaccinating only high-risk individuals and those aged ≥ 65 years was estimated to avert 274,313 cases, 33229 hospitalizations, 2,434 deaths, Malaysian ringgit (MYR) 576 million in direct medical costs, and MYR 579 million in indirect costs. Expanding vaccination coverage in the standard-risk population to 75% was estimated to avert more deaths (31%), hospitalizations (155%), infections (206%), direct costs (206%), and indirect costs (281%)., Conclusions: These findings support broader population Omicron-adapted bivalent booster vaccination in Malaysia with potential for significant health and economic gains.

Oral cancer (OC) is increasing worldwide, and it is mostly present to clinic in the late-stage of disease. Cancer of the lips, tongue, hard palate, upper and lower gingiva, buccal mucosa, and retromolar trigone are all included in the category of oral cavity cancer. Disease symptomatology and pathological grading decides the course of treatment. Several treatment modalities either alone in combinations may be utilized for oral squamous cell carcinoma (OSCC), including surgery, radiotherapy (external beam radiotherapy/brachytherapy), and adjuvant systemic therapy (chemotherapy or immunotherapy). Cancer patients also face a greater risk of oral side effects from chemotherapy, such as slowed tissue healing, bone, and salivary gland damage and disintegration, and disruption of the normal bacterial balance in the mouth. Consequently, the economic burden of the salivary gland, oral cavity, and oropharyngeal cancers must be also known for budget allocation, designing different programs and management strategies targeting oral cancers by any healthcare institutes. This article provides a summary of the most recent research that supports the use of chemotherapy for patients with advanced illness both alone and in conjunction with radiation including its adverse events and cost burden for oral cancers.

Ag-containing ZnO/ β-Ga 2 O 3 semiconductor, which exhibit reduced bandgap, increased light absorption, and hydrophilicity, have been found to be useful for photocatalytic CO 2 reduction and N 2 fixation by water. The charge-separation is facilitated by the new interfaces and inherent vacancies. The Ag@GaZn demonstrated the highest photocurrent response, about 20- and 2.27-folds that of the Ga and GaZn samples, respectively. CO, CH 4 , and H 2 formed as products for photo-reduction of CO 2 . Ag@GaZn catalyst exhibited the highest AQY of 0.121 % at 400 nm (31.2 W/m 2 ). Also, Ag@GaZn generated 740 μmolg -1 of NH 4 + ions, which was about 18-folds higher than Ga sample. In situ DRIFTS for isotopic-labelled 13 CO 2 and 15 N 2 reaffirmed the photo-activity of as-synthesized catalysts. Density functional theory provided insight into the relative affinity of different planes of heterostructures towards H 2 O, CO 2 and N 2 molecules. The structure-photoactivity rationale behind the intriguing Ag@GaZn sample offers a fundamental insight into the role of plasmonic Ag and design principle of heterostructure with improved photoactivity and stability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The human auditory system employs a number of principles to facilitate the selection of perceptually separated streams from a complex sound mixture. The brain leverages multi-scale redundant representations of the input and uses memory (or priors) to guide the selection of a target sound from the input mixture. Moreover, feedback mechanisms refine the memory constructs resulting in further improvement of selectivity of a particular sound object amidst dynamic backgrounds. The present study proposes a unified end-to-end computational framework that mimics these principles for sound source separation applied to both speech and music mixtures. While the problems of speech enhancement and music separation have often been tackled separately due to constraints and specificities of each signal domain, the current work posits that common principles for sound source separation are domain-agnostic. In the proposed scheme, parallel and hierarchical convolutional paths map input mixtures onto redundant but distributed higher-dimensional subspaces and utilize the concept of temporal coherence to gate the selection of embeddings belonging to a target stream abstracted in memory. These explicit memories are further refined through self-feedback from incoming observations in order to improve the system's selectivity when faced with unknown backgrounds. The model yields stable outcomes of source separation for both speech and music mixtures and demonstrates benefits of explicit memory as a powerful representation of priors that guide information selection from complex inputs., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2023.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 has continuously evolved, requiring the development of adapted vaccines. This study estimated the impact of the introduction and increased coverage of an Omicron-adapted bivalent booster vaccine in Thailand., Research Design and Methods: The outcomes of booster vaccination with an Omicron-adapted bivalent vaccine versus no booster vaccination were estimated using a combined cohort Markov decision tree model. The population was stratified into high- and standard-risk subpopulations. Using age-specific inputs informed by published sources, the model estimated health (case numbers, hospitalizations, and deaths) and economic (medical costs and productivity losses) outcomes in different age and risk subpopulations., Results: Booster vaccination in only the elderly and high-risk subpopulation was estimated to avert 97,596 cases 36,578 hospitalizations, 903 deaths, THB 3,119 million in direct medical costs, and THB 10,589 million in indirect medical costs. These benefits increased as vaccination was expanded to other subpopulations. Increasing the booster vaccination coverage to 75% of the standard-risk population averted more deaths (95%), hospitalizations (512%), infections (782%), direct costs (550%), and indirect costs (687%) compared to the base case., Conclusions: Broader vaccination with an Omicron-adapted bivalent booster vaccine could have significant public health and economic benefits in Thailand.

While plastics have revolutionized our world, plastic waste has serious environmental and economic impacts. Polyhydroxyalkanoic acid (PHA) is a bacterial carbon and energy reserve shown to be both biodegradable and biocompatible and could potentially replace conventional plastics. However, cost-effective mass production remains elusive. Bacteria often accumulate PHA as cytoplasmic granules. PHA synthase creates the PHA polymer from acetoacyl-CoA monomers, while phasins are small multifunctional proteins that are found in abundance on the granule surface. The PHA synthase gene from a novel marine isolate, Vibrio B-18 (or B-18), was placed in the presence or absence of an upstream phasin gene in a runaway replication plasmid using polymerase chain reaction (PCR) technology. Plasmid gene expression may be induced chemically or thermally. Overexpression of the PHA genes was demonstrated by SDS-PAGE analysis, and microscopy was used to detect PHA accumulation in three different enteric bacteria (Escherichia coli, Klebsiella aerogenes, and Shigella flexneri). While the B-18 genes were clearly overexpressed at 41°C, PHA accumulation occurred more readily at the lower (30°C) non-inducing temperature regardless of chemical induction if the phasin gene was present. A mutational analysis confirmed the identity of the start codon for the PHA synthase gene and provided evidence supporting the requirement for phasins to allow for PHA accumulation in the recombinant hosts. The findings described in this study confirm the conclusions obtained from related studies from other laboratories and lend support to the importance of including a phasin gene in addition to the basic genes needed for PHA synthesis and accumulation in recombinant enteric bacteria, such as Escherichia coli, Klebsiella aerogenes, and Shigella flexneri., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Kolibachuk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pediatric encephalitis has significant morbidity and mortality, yet 50% of cases are unexplained. Host genetics plays a role in encephalitis' development; however, the contributing variants are poorly understood. One child with anti-NMDA receptor encephalitis and ten with unexplained encephalitis underwent whole genome sequencing to identify rare candidate variants in genes known to cause monogenic immunologic and neurologic disorders, and polymorphisms associated with increased disease risk. Using the professional Human Genetic Mutation Database (Qiagen), we divided the candidate variants into three categories: monogenic deleterious or potentially deleterious variants (1) in a disease-consistent inheritance pattern; (2) in carrier states; and (3) disease-related polymorphisms. Six patients (55%) had a deleterious or potentially deleterious variant in a disease-consistent inheritance pattern, five (45%) were heterozygous carriers for an autosomal recessive condition, and six (55%) carried a disease-related polymorphism. Finally, seven (64%) had more than one variant, suggesting possible polygenetic risk. Among variants identified were those implicated in atypical hemolytic uremic syndrome, common variable immunodeficiency, hemophagocytic lymphohistiocytosis, and systemic lupus erythematosus. This preliminary study shows genetic variation related to inborn errors of immunity in acute pediatric encephalitis. Future research is needed to determine if these variants play a functional role in the development of unexplained encephalitis., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an affinity-enhanced mutant sBCMA-Fc fusion molecule (sBCMA-Fc V3) 4- and 500-fold stronger in binding to APRIL and BAFF, respectively. The mutant sBCMA-Fc V3 clone significantly enhanced antitumor activity against both MM and DLBCL. Importantly, we also demonstrated an adequate toxicity profile and on-target mechanism of action in nonhuman primate studies., (© 2022 Miao et al.)