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BackgroundPrenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results.MethodsWe evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software.ResultsNone of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups.ConclusionsThis large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups.ImpactGenetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

Introduction: Patients experiencing an out-of-hospital cardiac arrest (OHCA) frequently do not receive bystander cardiopulmonary resuscitation (CPR), especially in low- and middle-income countries (LMIC). In this study we sought to determine the prevalence of OHCA patients in Vietnam who received bystander CPR and its effects on survival outcomes.Methods: We performed a multicenter, retrospective observational study of patients (≥18 years) presenting with OHCA at three major hospitals in an LMIC from February 2014–December 2018. We collected data on the hospital and patient characteristics, the cardiac arrest events, the emergency medical services (EMS) system, the therapy methods, and the outcomes and compared these data, before and after pairwise 1:1 propensity score matching, between patients who received bystander CPR and those who did not. Upon admission, we assessed factors associated with good neurological survival at hospital discharge in univariable and multivariable logistic models.Results: Of 521 patients, 388 (74.5%) were men, and the mean age was 56.7 years (SD 17.3). Although most cardiac arrests (68.7%, 358/521) occurred at home and 78.8% (410/520) were witnessed, a low proportion (22.1%, 115/521) of these patients received bystander CPR. Only half of the patients were brought by EMS (8.1%, 42/521) or private ambulance (42.8%, 223/521), 50.8% (133/262) of whom had resuscitation attempts. Before matching, there was a significant difference in good neurological survival between patients who received bystander CPR (12.2%, 14/115) and patients who did not (4.7%, 19/406; P < .001). After matching, good neurological survival was absent in all OHCA patients who did not receive CPR from a bystander. The multivariable analysis showed that bystander CPR (adjusted odds ratio: 3.624; 95% confidence interval 1.629–8.063) was an independent predictor of good neurological survival.Conclusion: In our study, only 22.1% of total OHCA patients received bystander CPR, which contributed significantly to a low rate of good neurological survival in Vietnam. To improve the chances of survival with good neurological functions of OHCA patients, more people should be trained to perform bystander CPR and teach others as well. A standard program for emergency first-aid training is necessary for this purpose.

Scrub typhus is a leading cause of nonmalarial febrile illness in Southeast Asia (1). Scrub typhus is caused by miteborne Orentia tsutsugamushi infections, which until recently were thought to be [...]

Streptococcus gordonii is a Gram-positive bacterial species that typically colonizes the human oral cavity, but can also cause local or systemic diseases. Serine-rich repeat (SRR) glycoproteins exposed on the S. gordonii bacterial surface bind to sialylated glycans on human salivary, plasma, and platelet glycoproteins, which may contribute to oral colonization as well as endocardial infections. Despite a conserved overall domain organization of SRR adhesins, the Siglec-like binding regions (SLBRs) are highly variable, affecting the recognition of a wide range of sialoglycans. SLBR-N from the SRR glycoprotein of S. gordonii UB10712 possesses the remarkable ability to recognize complex core 2 O-glycans. We here employed a multidisciplinary approach, including flow cytometry, native mass spectrometry, isothermal titration calorimetry, NMR spectroscopy from both protein and ligand perspectives, and computational methods, to investigate the ligand specificity and binding preferences of SLBR-N when interacting with mono- and disialylated core 2 O-glycans. We determined the means by which SLBR-N preferentially binds branched α2,3-disialylated core 2 O-glycans: a selected conformation of the 3'SLn branch is accommodated into the main binding site, driving the sTa branch to further interact with the protein. At the same time, SLBR-N assumes an open conformation of the CD loop of the glycan-binding pocket, allowing one to accommodate the entire complex core 2 O-glycan. These findings establish the basis for the generation of novel tools for the detection of specific complex O-glycan structures and pave the way for the design and development of potential therapeutics against streptococcal infections.

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

Phoebe Mbabazi,1 Grace Banturaki,1 Suzan Naikoba,1 Esther M Nasuuna,1 Yukari C Manabe,1,2 Meredith Greene,3 Barbara Castelnuovo1 1Research Department, Infectious Disease Institute, College of Health Sciences, Makerere University, Kampala, Uganda; 2Division of Infectious Diseases, Department of Medicine, John Hopkins University, Baltimore, MD, USA; 3Division of General Internal Medicine & Geriatrics, Indiana University School of Medicine, Indianapolis, Indiana, USACorrespondence: Phoebe Mbabazi, Infectious Disease Institute, College of Health Sciences, Makerere University, P.O.box 22418, Kampala, Uganda, Email pmbabazi@idi.co.ugBackground: Older people living with HIV (PLHIV) are at high risk of developing geriatric syndromes. Data on geriatric syndromes among older PLHIV in sub-Saharan Africa are scarce. We examined sex differences in the prevalence and correlates of geriatric syndromes among PLHIV aged ≥ 60 years on antiretroviral therapy in Kampala, Uganda.Methods: This cross-sectional study analyzed data obtained during the enrollment of older PLHIV into a prospective observational cohort in Kampala. We used the Poisson regression model to explore the association between the number of geriatric syndromes and non-communicable diseases (NCDs), sociodemographic factors, and HIV-related factors.Results: We included 500 participants (48.8% women) with a median age of 64 years (interquartile range, IQR: 62.68). Almost all (94.4%) participants had at least one geriatric syndrome. More women were frail (13.1% vs 5.1%, P-value = 0.01) and had lower physical performance measured using the Short Physical Performance Battery (43.3% vs 26.6%, P-value < 0.01). Similarly, more women had cognitive impairment (83.2% vs 62.9%, P-value < 0.01) and reported falling (48.8% vs 34.0%, P-value < 0.01). Women (adjusted mean ratio, AMR 1.17, 95% CI 1.05– 1.30, P-value < 0.01), older age (AMR 1.11, 95% CI 1.07– 1.16, P-value < 0.01), no formal education (AMR 1.39, 95% CI 1.06– 1.82, P-value = 0.01), underweight (AMR 1.49, 95% CI 1.26– 1.76, P-value < 0.01), World Health Organization (WHO) stage 3 or 4 (AMR 1.11, 95% CI 0.01– 1.22, P-value = 0.04) and having two or more NCDs (AMR 1.11, 95% CI 1.00– 1.23, P-value = 0.04) were associated with a higher number of geriatric syndromes.Conclusion: The prevalence of geriatric syndromes was high among older PLHIV and was more common in women. There is a need to incorporate the screening and management of geriatric syndromes into the care of older PLHIV in sub-Saharan Africa, with a particular focus on women.Keywords: geriatric syndromes, HIV, older adults, sub-Saharan Africa

Abstract Shortly after the first case of SARS-CoV-2 was diagnosed a public health emergency (PHE) was declared and a multi-agency response was initiated within the US federal government to create and propagate testing capacity. As part of this response, an unprecedented program designated Rapid Acceleration of Diagnostics (RADx) Tech was established by the National Institutes of Health (NIH) to facilitate the development of point-of-care tests for the COVID-19. The RADx Tech Clinical Studies Core (CSC), located at the University of Massachusetts Chan Medical School (UMass Chan), with partnering academic, private, and non-governmental organizations around the country, was tasked with developing clinical studies to support this work. This manuscript details development of a biorepository specifically focused on the collection and storage of samples designed for diagnostic platform development. It highlights the unified collection and annotation process that enabled gathering a diverse set of samples. This diversity encompasses the geography and backgrounds of the participants as well as sample characteristics such as variant type and RT-PCR cycle threshold (CT) value of the corresponding reference sample on a uniform clinical reference platform.

Abstract Antarctic sea ice exerts great influence on Earth’s climate by controlling the exchange of heat, momentum, freshwater, and gases between the atmosphere and ocean. Antarctic sea ice extent has undergone a multidecadal slight increase followed by a substantial decline since 2016. Here we utilize a 300-yr sea ice data assimilation reconstruction and two NOAA/GFDL and five CMIP6 model simulations to demonstrate a multidecadal variability of Antarctic sea ice extent. Stronger westerlies associated with the Southern Annular Mode (SAM) enhance the upwelling of warm and saline water from the subsurface ocean. The consequent salinity increase weakens the upper-ocean stratification, induces deep convection, and in turn brings more subsurface warm and saline water to the surface. This salinity-convection feedback triggered by the SAM provides favorable conditions for multidecadal sea ice decrease. Processes acting in reverse are found to cause sea ice increase, although it evolves slower than sea ice decrease.

X-linked NF-κB essential modulator (NEMO) deficiency is a primary immunodeficiency characterized by combined immunodeficiency and ectodermal dysplasia. Monocytes from the patients demonstrate a severely impaired response to tissue necrosis factor or lipopolysaccharide, whereas hyper-inflammation is found in some patients. Juvenile myelomonocytic leukemia (JMML) is a pediatric malignancy caused by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and aberrant RAS signaling activation. Patients with JMML demonstrate characteristic manifestations such as splenomegaly, monocytosis and the presence of myeloid or erythroid precursors in the peripheral blood. Here, we present the case of a male infant with ectodermal dysplasia, bacterial septicemia, Pneumocystis pneumonia, severe inflammation and transient manifestations mimicking JMML. Genetic analysis revealed a deep intronic germline variant of IKBKG. Full-length IKBKG cDNA and NEMO protein expression were almost inexistent. Peripheral mononuclear cells (PBMCs) from the patient showed increased RAS signaling activation with GM-CSF or Phorbol 12-myristate 13-acetate without the RAS-associated gene variant, although the increased RAS signaling activation in induced-pluripotent stem cell-derived myeloid lineage and bone marrow-derived mesenchymal cells was not evident. The patient with NEMO deficiency demonstrated JMML-like manifestation and severe inflammation. PBMCs of the patient demonstrated increased RAS signaling activation with unknown pathophysiology.

Abstract Background Microplastics (MPs), plastic particles

Abstract Biomimetic chemical logic gates that can reversibly transform their shape and physical properties in response to their environment are an important research field. Most artificial chemical logic gates, however, rely on changes in the microscopic properties of molecules and ions in solution. Hence, developing chemical logic gates that influence macroscopic properties, such as crystal structures and magnetic and electrical properties, is essential for mimicking in vivo phenomena more accurately. Here, we develop a reset-set flip-flop circuit based on a single crystal that reversibly transforms in the presence of Ca2+ ions in aqueous solutions and is analogous to the chemical logic gate in muscles. During the crystal transformation, the lattice volume undergoes ~39% shrinkage, and the magnetic and electrical properties change considerably. Compared with existing products, the constructed crystalline system more closely resembles the function of actual muscles, which is promising for advancing the field of biomimetics.

Abstract Background Imaging examination of cerebral blood flow (CBF), oxygen extraction fraction (OEF), and metabolic rate of oxygen is crucial for understanding the normal functioning and pathophysiology of the brain. A recently developed method estimates the appearance time of cerebral blood (ATB) pixel-wise from the imaging examination of CBF alone. In this study, we aimed to test the potential of ATB as an indicator of OEF. Results We retrospectively reviewed patients (n = 62) with suspected cerebrovascular disorders including steno-occlusive disease who underwent positron emission tomography (PET) with 15O-labelled tracers. Regarding the generated OEF and ATB images, a visual assessment was performed to test the consistency of the elevated OEF and delayed ATB. The OEF and ATB values and the absolute differences between their ipsilateral and contralateral sides were extracted and obtained for the entire hemisphere and the middle, anterior, and posterior cerebral arterial regions. Consistency was observed in 52 PET scans (83.9%) in visual assessment. The OEF and ATB values were moderately correlated (r = 0.553, p

Abstract Haploinsufficiency of the transcriptional repressor ZBTB18/RP58 is associated with intellectual disability. However, the mechanisms causing this disability are unknown, and preventative measures and treatments are not available. Here, we assessed multiple behaviors in Zbtb18/Rp58 heterozygous-knockout mice, and examined local field potentials, DNA fragmentation, mitochondrial morphology, and performed histochemical and transcriptome analyses in the hippocampus to evaluate chronic inflammation. In wild-type mice, object location memory was present at a similar level at 2 and 4–5 months of age, and became impaired at 12–18 months. In contrast, Zbtb18/Rp58 heterozygous-knockout mice displayed early onset impairments in object location memory by 4–5 months of age. These mice also exhibited earlier accumulation of DNA and mitochondrial damage, and activated microglia in the dentate gyrus, which are associated with defective DNA repair. Notably, chronic minocycline therapy, which has neuroprotective and anti-inflammatory effects, attenuated age-related phenotypes, including accumulation of DNA damage, increased microglial activation, and impairment of object location memory. Our results suggest that Zbtb18/Rp58 activity is required for DNA repair and its reduction results in DNA and mitochondrial damage, increased activation of microglia, and inflammation, leading to accelerated declines in cognitive functions. Minocycline has potential as a therapeutic agent for the treatment of ZBTB18/RP58 haploinsufficiency-associated cognitive dysfunction.

Abstract Masticatory muscle forces influence craniofacial morphology development. The antegonial notch (Notch) is a bony concavity on the inferior border of the mandible. Considering the Notch is located anteriorly to the insertion of the masseter muscle and varies among individuals, we hypothesised that these muscles influence the formation of the Notch. Therefore, this study aimed to investigate the correlation between mandible morphology and Notch formation. Sixty Japanese patients who visited the Department of Orthodontics at our university hospital were retrospectively evaluated. Morphological and morphometric analyses of the Notch and related craniofacial parameters were conducted using lateral cephalograms taken at the patients’ initial visits. Standard values for the Notch area and depth were determined, and the morphology of the Notch and mandible was analysed using Spearman’s rank correlation coefficient (p

Abstract Background Adenocarcinoma of the esophagogastric junction (AEGJ) is most common in men and the elderly, but the disease is becoming more common in female and young adult persons. We have investigated the clinicoepidemiological characteristics of female and young adult patients with AEGJ and the 12-year trends in the Kurashiki area for young adult patients with AEGJ. Methods Patients diagnosed with AEGJ in 12 hospitals between January 2008 and December 2019 were included in this study. Patients were divided into three groups by age (young adult [≤50 years], middle-aged [51 to 70 years], and elderly [>70 years]). Factors associated with AEGJ such as obesity, smoking, hiatal hernia and male, which were reported in our previous study, were identified. Results One hundred and eighty-eight AEGJ patients, including 36 females and 20 young adults, were characterized. There was no significant change in the annual incidence of AEGJ among female (p=0.078) and young adult patients (p=0.89). Female patients without any associated factors, accounting for 53% (19/36) of the female patients and young adult patients, had significantly more histologically undifferentiated cancers than patients with at least one associated factor (58% [11/19] vs. 30% [50/169], p=0.025) and middle-aged and elderly patients (60% [12/20] vs. 30% [25/83] vs. 28% [24/85], p =0.026). Smoking was significantly less common in women than in men (8% [3/36] vs. 57% [87/152], p < 0.01). There were no significant differences between ages in the proportions of these associated factors. Conclusions Histologically undifferentiated AEGJ cancers were more frequent in female patients without any associated factors and in young adult patients. Factors associated with AEGJ may differ between women and men, but they are similar in young adults and older adults. No increase in young adult patients with AEGJ was observed in the 12-year study.

Abstract Background The relationship between the combination of platelet count and neutrophil‐lymphocyte ratio (COP‐NLR) and prognosis in patients with advanced non‐small cell lung cancer (NSCLC) treated with immune checkpoint inhibitor (ICI) combination therapy with chemotherapy remains unclear. Thus, we investigated prognostic factors, including the COP‐NLR, to identify patients who could benefit from the therapeutic efficacy of ICI combination therapy for advanced NSCLC. Furthermore, we evaluated the relationship between the COP‐NLR score during ICI combination therapy and treatment response. Methods We conducted a retrospective cohort study of 88 patients with NSCLC who initially received ICI combination therapy. The primary outcome was overall survival (OS). The prognostic factors were extracted using the Cox proportional hazards model. The relationship between COP‐NLR score at 3 weeks after starting ICI combination therapy and a good response (complete response [CR] and partial response [PR]) to treatment was analyzed using the chi‐square test. Results The median OS was 15.7 months. In the multivariable analysis, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2, distant metastatic sites ≥2, and baseline COP‐NLR scores of 1, 2 were extracted as significant poor prognostic factors. The proportion of patients with CR and PR in the 3‐week COP‐NLR score of 0 group was significantly higher than that in scores of 1, 2 group. Conclusions Baseline COP‐NLR, ECOG PS, and number of distant metastatic sites were prognostic factors in patients with NSCLC with ICI combination therapy. A lower 3‐week COP‐NLR was associated with a good response to treatment.

This paper proposes a method for identifying the bicycle riding environment using only onboard equipment. Initially, a fundamental subsystem is established for identifying the bicycle riding environment, and its functionality is validated. The findings indicate that the subsystem, utilizing an open-source trained model, can detect riding on roadways but not on sidewalks. Consequently, we emphasize the need for transfer learning, specifically using sidewalk viewpoint images, to enable the identification of bicycle riding environments. Subsequently, we conduct bicycle riding environment identification by employing a transfer learning model with manually labeled training data. The results demonstrate that after transfer learning, sidewalk riding detection, which was previously unachievable, becomes feasible. The identification rate was over 80%. Furthermore, we develop four riding environment identification algorithms, including the transfer learning model, and compare their performance across various road environments and riding conditions. Consequently, it is established that the region of interest (ROI) extension identification algorithm exhibits the highest identification performance (93% on average). As a result, this paper contributes valuable insights into the realization of bicycle riding environment identification, particularly in the context of detecting traffic violations within the riding safety support information system.

In this study, we conducted bicycle riding experiments that focus on the method of information presentation by an automated system to cyclists, with the intent to design an information system related to bicycle safety information. In an evaluation of information presentation, we confirmed that auditory presentation was the most effective from the viewpoints of both recognition and comprehension. In addition, information presented using the auditory method was more likely to be recognized than information presented using the visual and tactile method combined. The results of the analysis of variance for recognition showed that the visual presentation method had no significant effect. In addition, the experiments involved behavioral observation using the system and a questionnaire survey on changes in behavior before and after experiencing the system. The results showed that information was correctly conveyed by the system using a combination of auditory, tactile, and visual presentation methods, regardless of the users' degree of awareness of the system. Two weeks after the experiment, a survey was conducted to investigate the changes in the participants' awareness and behavior regarding risky or illegal riding. The results showed an improvement in the awareness of risky or illegal riding in daily life and an increase in right behavior, confirming the effectiveness of this system. Consequently, the results demonstrate the effectiveness of the system and provide knowledge for realizing a bicycle riding safety support information system.