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Background: The standard of care for unresectable locally advanced NSCLC is concurrent chemotherapy and radiation (CRT) followed by adjuvant durvalumab, established by the PACIFIC trial, which revealed acceptable although higher rates of pneumonitis with durvaluamb than placebo. We retrospectively reviewed patients with locally advanced NSCLC from 2018 to 2022 treated with definitive CRT (≥60 Gy) followed by at least one dose of adjuvant durvalumab. Objective: To review the incidence of pneumonitis and contributing factors, and also to review grade 5 pneumonitis (G5) events. Methods: We identified 78 cases with a median age of 70.0 years and a median follow-up of 36 months. All patients received CRT of at least 60 Gy at 2 Gy per fraction. A total of 22 patients (28.2%) completed 12 months of durvalumab. The cumulative incidence of any-grade pneumonitis was 28.2%. Pneumonitis rate in grades 1, 2, 3, 4, and 5 was 1.3%, 10.3%, 7.7%, 0.0%, and 9.0%, respectively. Results: Multivariate analysis did not reveal significant factors associated with G5 pneumonitis. There were 8 patients who received radiation therapy doses above standard limits and, of these, only two developed G5 pneumonitis. All patients with G5 pneumonitis had multiple comorbidities or previous malignancy treated with systemic therapy. The median overall survival was 31.1 months and the median progression-free survival was 12.7 months. Conclusions: We report comparable overall rates of pneumonitis relative to published data with higher rates of G5 pneumonitis. Patients with high-dose radiation therapy (≥60 Gy) and Eastern Cooperative Oncology Group performance status greater than or equal to 2 may tolerate adjuvant durvalumab, though providers should exercise caution in patients with extensive comorbidities.

Background: The challenging working conditions experienced by community health workers (CHWs) have an impact on their mental health, as detected by the NGO Compañeros En Salud (CES) in rural Mexico. In response to this situation, CES designed through a participatory process a package of interventions to promote the mental well-being of CHWs, beginning implementation in 2021. The objective of the present study was to learn how CES CHWs' work affects their mental well-being and to evaluate the intervention package to promote CHWs’ mental well-being implemented by CES. Methods: In June–August 2023, 52 CHWs from the CES-supported communities participated in the study, responding to a survey and participating in 10 focus group discussions. Quantitative data were analyzed using statistical descriptive analysis and qualitative data using thematic analysis. Findings: Participants highlighted the impact on their communities as one of the main aspects of their job that contribute positively to their mental well-being, as well as the challenging work-life balance as one of the main aspects that contribute negatively. As for the interventions, most participants considered them significant and positive for their mental well-being, highlighting positive aspects such as the possibility of creating community with their peers or a feeling of self-efficacy. However, the access to interventions was uneven among participants and most interventions presented areas for improvement, such as the periodicity of psychological distress screening or the response time to material needs. Conclusions: Efforts to support CHW well-being in the areas they signal as needs can impact their experiences around work and their perceived well-being. Access to work materials, preparedness on clinical topics, and relationships with their teams are key areas that may have a bearing on CHWs' emotional and mental well-being. Interventions aimed at these areas can positively impact CHWs’ self-efficacy, their community with each other, and their interactions with patients.

ABSTRACT: Background: Pain, disability and progressive kyphosis is a common problem after traumatic injury of the thoracolumbar (TL-) junction. Surgical treatment may include long-segment posterior or short-segment anterior-posterior fusion. We aim to report our experience with the application of short-segment posterior instrumented fusion with anterior column support using lateral lumbar or thoracic interbody (LLIF) cages. Methods: In this retrospective, single-center observational cohort study we included consecutive patients treated surgically for traumatic injury of the TL-junction (Th10/11-L2/3) by posterior instrumentation/fusion and LLIF. We measured segmental kyphosis, complications, and outcomes until last follow-up (about 3 years postoperative). Results: We identified 61 patients (mean age 39.0 years [SD 13.3]; 23 females [37.7%]) with A3 fractures without (n=48; 78.7%) or with additional sagittal split component n=11; 18.0%. Additional posterior tension band injury was present in n=26 (42.6%). The affected levels of injury were Th12/L1 in n=25 (41.0%) and Th11/12 in n=22 (36.1%). The segmental kyphotic angle was 14.6° (6.7°) preoperative and remained significantly reduced at all times of follow-up at discharge (5.4°±5.5°; p

ABSTRACT: Background: Transforaminal anterior release (TFAR) is a technical extension of the transforaminal lumbar interbody fusion (TLIF) procedure with deliberate release of the anterior longitudinal ligament (ALL). Methods: In a retrospective, single-center observational cohort study, consecutive adult patients undergoing TLIF surgery at L4/L5 and/or L5/S1 between 01/2018 and 12/2022 for degenerative disc disease or deformity were considered. The TFAR group (with ALL release) was compared to a standard TLIF group (without ALL release), matched in a 1:3 ratio. Uni- and multivariable logistic regression models were built to estimate the likelihood of any adverse event (AE), reoperation, and excellent/good clinical outcome at 12 months. Results: Of 438 patients, 18 undergoing TFAR were matched to 53 undergoing standard TLIF. TFAR procedures were frequently part of extensive, anterior-posterior or multilevel fusion procedures with longer surgery time and higher blood loss. The rates of intraoperative surgical AEs were similar (16.7 vs. 11.3%, p=.789). The rates and severities of surgical AEs, as well as reoperation rates and clinical outcomes were similar at time of discharge, 90 days, and 12 months postoperatively (all p>.05). TFAR allowed for an increase in total lumbar lordosis of 16.1° and in lumbar lordosis between L4 and S1 of 16.3° at discharge, which was maintained during follow-up. In both the uni- and multivariable models, patients undergoing TFAR were as likely as patients undergoing standard TLIF to experience any AE (adjusted OR 0.78, 95% CI 0.21–2.94), any reoperation (aOR 0.46, 95% CI 0.11–1.90) or excellent/good clinical outcome at 12 months (aOR 2.01, 95% CI 0.52–7.74). Conclusions: The TFAR technique has a safety profile which is comparable to the standard TLIF procedure, but it allows for a greater restoration of lumbar lordosis at L4-S1. We suggest considering the TFAR technique in selected patients with sagittal imbalance and mobile segments for restoration of lumbar lordosis.

Summary: Trained immunity is characterized by histone modifications and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to heightened responsiveness to secondary stimuli. Although our understanding of the molecular regulation of trained immunity has increased, the role of adaptive immune cells herein remains largely unknown. Here, we show that T cells modulate trained immunity via cluster of differentiation 40-tissue necrosis factor receptor-associated factor 6 (CD40-TRAF6) signaling. CD40-TRAF6 inhibition modulates functional, transcriptomic, and metabolic reprogramming and modifies histone 3 lysine 4 trimethylation associated with trained immunity. Besides in vitro studies, we reveal that single-nucleotide polymorphisms in the proximity of CD40 are linked to trained immunity responses in vivo and that combining CD40-TRAF6 inhibition with cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)-mediated co-stimulatory blockade induces long-term graft acceptance in a murine heart transplantation model. Combined, our results reveal that trained immunity is modulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells and that this can be leveraged for therapeutic purposes.

Summary: Background: Access to gender-affirming medical care has life-saving effects on transgender and gender diverse (TGD) individuals. An increasing number of TGD individuals seek care which led to waiting times of years. We assessed the duration and effects of excessive waiting for gender-affirming care. Methods: In this mixed-methods cross-sectional population study, conducted in the Netherlands between June and August 2019, all TGD individuals with experiences with receiving/applying for gender-affirming medical care could participate. Data of participants waiting for care was primarily analyzed. Demographic characteristics and requested care (multiple-choice questions) and the effects of waiting on health were surveyed (open-ended questions). Descriptive statistics were calculated per treatment, and differences in participant characteristics between those waiting for and already in care were assessed through Chi squared tests and post-hoc testing of residuals. Open text answers were thematically analyzed. Findings: Of all 975 participants, 431 (44.2%) waited for gender-affirming medical care. For 10 out of 20 treatment modalities, the median waiting period was more than a year. Participants already in care were on average higher educated and less-frequently non-binary. Subjective effects of waiting were (very) negative for most treatments. Qualitative findings showed that long waiting was associated with a range of psychosocial distress, poorer health, increasing healthcare consumption, and increased inequality between TGD individuals. Interpretation: Findings confirm that TGD individuals encounter long waiting times in multiple stages of their gender-affirming medical care. Waiting affects both physical and psychosocial health. Individual resilience and resources can mitigate these experiences, which increase inequality within this already marginalized group. Funding: Ministry of Health, Welfare and Sport of the Netherlands and Zorgverzekeraars Nederland (Healthcare Insurers Netherlands).

Background: Reduced cardiac energy is a hallmark feature of heart failure and is common in cardiac amyloidosis (CA) and can be aggravated by the presence of iron deficiency. Methods: Retrospective analysis of a single tertiary care center CA registry. Prevalence of iron deficiency was determined based on two definitions: (1) Classic definition, ferritin < 100 µg/L irrespective of transferin saturation (TSAT) or ferritin between 100 and 300 µg/L with a TSAT < 20%, and (2) TSAT-based definition, TSAT < 20%. Results: Out of a total of 393 CA patients who had a full set of iron indices (44% light chain [AL]-CA, 50% transthyretin [ATTR]-CA, remainder other or unspecified CA subtype), 56% had iron deficiency according to the classic definition and 58% according to the TSAT definition, with similar prevalence in AL-CA vs ATTR-CA (p = .135). Per both definitions 58% had anemia. Only the TSAT-based definition was associated with worse functional status (p = .039) and worse cardiac function. CA patients with a TSAT < 20% illustrated features of more pronounced right ventricular (RV) failure including lower TAPSE on echocardiography, lower RV ejection fraction and RV stroke volume index on CMR, increased right-sided filling pressures, lower pulmonary artery pulsatility index, and higher RAP/PCWP ratio by right heart catheterization. Neither the classic nor the TSAT-based definition was associated with a higher risk of all-cause mortality after covariate adjustment. Conclusion: Iron deficiency is common in cardiac amyloidosis and, when identified with a TSAT < 20%, is associated with worse functional status and more pronounced RV disease, but not with a higher risk of all-cause mortality.

Following harvest, monitoring reforestation success is a crucial component of sustainable management. In Alberta, Canada, like other jurisdictions, the efficiency of the current plot-based forest regeneration monitoring regime is challenged by the cost of accessibility and the declining availability of qualified field crews. Fine spatial resolution imagery and deep learning have been proposed as alternative monitoring tools and have proven successful under experimental conditions, yet how successfully models can be applied and transferred between a range of untrained sites and conditions remains unclear.In this research, we repurposed a mask region-based convolutional neural network (Mask R–CNN) model that was previously trained to delineate coniferous tree crowns to instead segment instances of two species of regenerating conifers. We transferred learned parameters by replacing original single-class labels with photo-interpreted species information and retraining a selection of the network's parameters. We assessed the transferability of the new model by testing on five untrained sites, representing a range of forest types and densities typical of reforestation in the region. Results yielded a mean average precision (mAP) of 72% and average class F1 scores of 69% and 78% for lodgepole pine (Pinus contorta) and white spruce (Picea glauca), respectively, demonstrating successful transferability. We then investigated an additional transfer learning scenario by iteratively adding data from four of the five sites to the training set while reserving data from the remaining site for testing. On average, this improved mAP by 5%, lodgepole pine F1 by 7%, and white spruce F1 by 3%, and demonstrated that trained models can be continuously improved as sufficiently representative data becomes available.

Summary: Tumor tissues often contain high extracellular adenosine, promoting an immunosuppressed environment linked to mesenchymal transition and immune evasion. Here, we show that loss of the epithelial transcription factor, GRHL2, triggers NT5E/CD73 ecto-enzyme expression, augmenting the conversion of AMP to adenosine. GRHL2 binds an intronic NT5E sequence and is negatively correlated with NT5E/CD73 in breast cancer cell lines and patients. Remarkably, the increased adenosine levels triggered by GRHL2 depletion in MCF-7 breast cancer cells do not suppress but mildly increase CD8 T cell recruitment, a response mimicked by a stable adenosine analog but prevented by CD73 inhibition. Indeed, NT5E expression shows a positive rather than negative association with CD8 T cell infiltration in breast cancer patients. These findings reveal a GRHL2-regulated immune modulation mechanism in breast cancers and show that extracellular adenosine, besides its established role as a suppressor of T cell-mediated cytotoxicity, is associated with enhanced T cell recruitment.

Summary: Background: The principal barrier to an HIV cure is the presence of the latent viral reservoir (LVR), which has been understudied in African populations. From 2018 to 2019, Uganda instituted a nationwide rollout of ART consisting of Dolutegravir (DTG) with two NRTI, which replaced the previous regimen of one NNRTI and the same two NRTI. Methods: Changes in the inducible replication-competent LVR (RC-LVR) of ART-suppressed Ugandans with HIV (n = 88) from 2015 to 2020 were examined using the quantitative viral outgrowth assay. Outgrowth viruses were examined for viral evolution. Changes in the RC-LVR were analyzed using three versions of a Bayesian model that estimated the decay rate over time as a single, linear rate (model A), or allowing for a change at time of DTG initiation (model B&C). Findings: Model A estimated the slope of RC-LVR change as a non-significant positive increase, which was due to a temporary spike in the RC-LVR that occurred 0–12 months post-DTG initiation (p

Background:: Female urethral diverticula (UD) are rare and when one is present, it often receives a delayed diagnosis. Limited data is present on long-term and patient-related outcomes of a diverticulectomy. We aim to evaluate the clinical presentation of UD and to assess both objective and subjective effects of diverticulectomy in women. Methods: In this retrospective study, patient files of female patients with a UD from two tertiary hospitals were reviewed. Data collected from patient files included symptoms at presentation, surgery reports and complications. Patients were interviewed over the phone to evaluate the long-term impacts of surgery. The primary outcome was defined as subjective resolution of symptoms after diverticulectomy on short-term and long- term follow-up. Secondary outcomes included complications, time from the start of symptoms until diagnosis, recurrence risk and anatomical diverticulum characteristics relevant for success of surgery. Results:: 21 women were included. Urethral swelling was reported as a main symptom at presentation in 48%. Vaginal pain was the main symptom in 33% of the patients. Comparing the symptoms before diverticulectomy to the symptoms after surgery, at a mean follow-up of 36 months (range 6–78), there was a significant resolution of the sensation of a vaginal mass, dyspareunia, discharge and recurrent urinary tract infections (p < 0.05). A sensation of post-void residual, terminal dribbling and stress urinary incontinence (SUI) were reported more often after surgery than before (p < 0.05). De novo SUI was seen in 45% of the patients. Of the patients with a partially dorsally located diverticulum and those without involvement of the dorsal side of the urethra, respectively 50% and 43% experienced de novo SUI in the long-term (p = 0.57). 50% of the women were without any symptoms in the long-term and 35% reported fewer symptoms than before surgery. In four patients (20%) a recurrence was identified after surgery. Conclusion:: Urethral swelling and vaginal pain are the two main symptoms of a UD. In 50% of the patients diverticulectomy results in complete resolution of symptoms and in 35% of the patients it leads to fewer symptoms. Diverticulectomy entails a considerable risk (45%) of de novo SUI, of which patients should be informed pre-operatively.

Background: Angiotensin II receptor blockers (ARBs) have been associated with preventing posttraumatic stress disorder symptom development and improving memory. However, the underlying neural mechanisms are poorly understood. This study investigated ARB effects on memory encoding and hippocampal functioning that have previously been implicated in posttraumatic stress disorder development. Methods: In a double-blind randomized design, 40 high-trait-anxious participants (33 women) received the ARB losartan (50 mg) or placebo. At drug peak level, participants encoded images of animals and landscapes before undergoing functional magnetic resonance imaging, where they viewed the encoded familiar images and unseen novel images to be memorized and classified as animals/landscapes. Memory recognition was assessed 1 hour after functional magnetic resonance imaging. To analyze neural effects, whole-brain analysis, hippocampus region-of-interest analysis, and exploratory multivariate pattern similarity analysis were employed. Results: ARBs facilitated parahippocampal processing. In the whole-brain analysis, losartan enhanced brain activity for familiar images in the parahippocampal gyrus (PHC), anterior cingulate cortex, and caudate. For novel images, losartan enhanced brain activity in the PHC only. Pattern similarity analysis showed that losartan increased neural stability in the PHC when processing novel and familiar images. However, there were no drug effects on memory recognition or hippocampal activation. Conclusions: Given that the hippocampus receives major input from the PHC, our findings suggest that ARBs may modulate higher-order visual processing through parahippocampal involvement, potentially preserving intact memory input. Future research needs to directly investigate whether this effect may underlie the preventive effects of ARBs in the development of posttraumatic stress disorder.

Introduction: Reports about lateral lumbar or thoracic interbody fusion (LLIF) using expandable interbody spacers are sparse. Research question: To report our experience with the use of expandable spacers for LLIF. Material and methods: We reviewed all consecutive LLIF patients with use of an expandable titanium interbody implant (ELSA® Expandable Integrated LLIF Spacer, Globus Medical Inc, PA (USA)) between September 2018 and January 2024. Results: We identified 503 patients, in which we performed LLIF at 732 levels. In 63 patients (12.5%) and 70 levels (9.6%) an expandable spacer was used. The mean age was 61.4 years, 57.1% were females. LLIF was performed between T11/12 – L4/5 in the setting of fusion procedures (mono-/bisegmental (20; 28.6%), 3–7 segments (29; 41.4%); >7 segments (21; 30.0%)), of which 21 (33.3%), 20 (31.8%) and 22 (34.9%) were for traumatic, deformity/revision and other diagnoses. Surgery included release of the anterior longitudinal ligament in 30 cases (42.9%). Intraoperative adverse events (AEs) were noted in 2 (3.2%), postoperative AEs in 27 (42.9%) at discharge, 17 (27.0%) at 3 months and 14 (22.2%) at 12 months. Segmental sagittal Cobb angle changed from 1.3° (preoperative) to 13.0° at discharge (p

K12 private tutoring (shadow education) supplementing mainstream education is popular in China. K12 shadow education companies aiming to succeed in both private business and public school competitions need to figure out what factors affect their success. Most studies about Chinese K12 shadow education focused on the development and status from the perspective of education and society. This paper uses quantitative and qualitative methods to collect and analyze data from questionnaires and in-depth interviews. The data from in-depth interviews support and supplement the data from questionnaires. From the management viewpoint, this paper provides a new model for K12 shadow education companies. It comes up with the idea that human resource management and customer service are the critical factors for 12 shadow education companies to succeed. This study provides meaningful references for the more rational development of K12 education companies in an ever-changing social environment.

Background: Immunosuppressive treatment in heart transplant (HTx) recipient causes osteoporosis. The urinary proteomic profile (UPP) includes peptide fragments derived from the bone extracellular matrix. Study aims were to develop and validate a multidimensional UPP biomarker for osteoporosis in HTx patients from single sequenced urinary peptides identifying the parent proteins. Methods: A single-center HTx cohort was analyzed. Urine samples were measured by capillary electrophoresis coupled with mass spectrometry. Cases with osteoporosis and matching controls were randomly selected from all available 389 patients. In derivation case-control dataset, 1576 sequenced peptides detectable in ≥30 % of patients. Applying statistical analysis on these, an 18-peptide multidimensional osteoporosis UPP biomarker (OSTEO18) was generated by support vector modeling. The 2 replication datasets included 118 and 94 patients. For further validation, the whole cohort was analyzed. Statistical methods included logistic regression and receiver operating characteristic curve (ROC) analysis. Results: In derivation dataset, the AUC, sensitivity and specificity of OSTEO18 were 0.83 (95 % CI: 0.76–0.90), 74.3 % and 87.1 %, respectively. In replication datasets, results were confirmatory. In the whole cohort (154 osteoporotic patients [39.6 %]), the ORs for osteoporosis increased (p

ABSTRACT: Screening for genetic diversity in livestock species breeds is of utmost importance, especially for local, small populations that are at the risk of extinction. Luckily, recent developments in technology increase access to genotyping, also for numerically small breeds. One of these new technologies is the IMAGE001 single nucleotide polymorphism genotyping array that includes markers for 6 different species (cow, pig, sheep, chicken, horse and goat). For our current study, we studied the Turkey-headed Malines chicken, a local chicken breed in Belgium, for the first time. A total of 110 animals were genotyped, together with 29 samples from 4 supposedly related breeds. The genotypes were used to assess the genetic diversity of this local breed. Our analysis revealed an average inbreeding coefficient of 0.20 through runs of homozygosity analysis, and effective population size estimation based on linkage disequilibrium indicated a low genetic diversity (Ne = 34). Moreover, a principal component analysis and a genetic differentiation study (FST) were performed using these marker data to position the Turkey-headed Malines relative to the 4 other indigenous Belgian chicken breeds. Finally, we discussed the practical implications of the overlap between the IMAGE001 array and other existing chicken genotyping arrays. This study is the first use of the novel IMAGE001 array to evaluate a local chicken breed, and demonstrates it as a viable option for genomic characterization a breed. Moreover, with this research, we are able to provide a good basis for further evaluation of the Belgian chicken heritage.

ABSTRACT: Objectives: Long-term care facilities (LTCFs) have been disproportionately impacted by COVID-19. Yet, the reasons why certain LTCFs are affected more by outbreaks are poorly understood. This study aimed to identify the facility- and ward-level factors associated with SARS-CoV-2 outbreaks among LTCF residents. Methods: We conducted a retrospective cohort study of multiple Dutch LTCFs (N = 60; with 298 wards providing care for ∼5600 residents) from September 2020 to June 2021. A dataset was constructed linking SARS-CoV-2 cases among LTCF residents to facility- and ward-level factors. Multilevel logistic regression analyses examined the associations between these factors and the likelihood of a SARS-CoV-2 outbreak among residents. Results: During periods of the Classic variant, the mechanical recirculation of air was associated with significantly increased odds of a SARS-CoV-2 outbreak. During periods of the Alpha variant, the factors associated with significantly increased odds included large ward size (≥21 beds), wards providing psychogeriatric care, fewer restrictions on staff movement between wards and facilities, and a greater number of cases among staff (>10 cases). Conclusion: Policy and protocols on reducing resident density, staff movement, and mechanical recirculation of air in buildings are recommended to enhance outbreak preparedness in LTCFs. The implementation of low-threshold preventive measures among psychogeriatric residents is important because they appear as a particularly vulnerable group.

Modern laser scanners, depth sensor devices and Dense Image Matching techniques allow for capturing of extensive point cloud datasets. While capturing has become more user-friendly, the size of registered point clouds results in large datasets which pose challenges for processing, storage and visualization. This paper presents a decomposition scheme using oriented KD trees and the wavelet transform for unordered point clouds. Taking inspiration from image pyramids, the decomposition scheme comes with a Level of Detail representation where higher-levels are progressively reconstructed from lower ones, thus making it suitable for streaming and continuous Level of Detail. Furthermore, the decomposed representation allows common compression techniques to achieve higher compression ratios by modifying the underlying frequency data at the cost of geometric accuracy and therefore allows for flexible lossy compression. After introducing this novel decomposition scheme, results are discussed to show how it deals with data captured from different sources.

Assays to quantify natural killer (NK) cell killing efficacy have traditionally focused on assessing either direct killing or antibody dependent cell-mediated cytotoxicity (ADCC) independently. Due to the probability that immunotherapeutic interventions affect NK cell-mediated direct killing and NK cell-mediated ADCC differently, we developed an assay with the capacity to measure NK cell-mediated direct killing and ADCC simultaneously with cells from the same human donor. Specifically, this design allows for a single NK cell population to be split into several experimental conditions (e.g., direct killing, ADCC), thus controlling for potential confounders associated with human-to-human variation when assessing immunotherapy impacts. Our Natural Killer cell Simultaneous ADCC and Direct Killing Assay (NK-SADKA) allows researchers to reproducibly quantify both direct killing and ADCC by human NK cells. Furthermore, this optimized experimental design allows for concurrent analysis of the NK cells via flow cytometric immunophenotyping of NK cell populations which will facilitate the identification of relationships between NK cell phenotype and the subsequent killing potential. This assay will be valuable for assessing the broader impact(s) of immunotherapy strategies on both modes of NK cell killing.

Summary: Selective autophagy mediates the removal of harmful material from the cytoplasm. This cargo material is selected by cargo receptors, which orchestrate its sequestration within double-membrane autophagosomes and subsequent lysosomal degradation. The cargo receptor p62/SQSTM1 is present in cytoplasmic condensates, and a fraction of them are constantly delivered into lysosomes. However, the molecular composition of the p62 condensates is incompletely understood. To obtain insights into their composition, we develop a method to isolate these condensates and find that p62 condensates are enriched in components of the translation machinery. Furthermore, p62 interacts with translation initiation factors, and eukaryotic initiation factor 2α (eIF2α) and eIF4E are degraded by autophagy in a p62-dependent manner. Thus, p62-mediated autophagy may in part be linked to down-regulation of translation initiation. The p62 condensate isolation protocol developed here may facilitate the study of their contribution to cellular quality control and their roles in health and disease.

Summary: Innate immune memory, also called ''trained immunity,'' is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.

Introduction: Little is known about the clinical characteristics of women at increased risk for abnormal uterine bleeding (UB) during anticoagulation for venous thromboembolism (VTE). Methods: We used the RIETE registry to identify the baseline characteristics of women developing abnormal UB during anticoagulation. We used logistic regression analysis to identify independent predictors for abnormal UB. Then, we built a prognostic score to identify at-risk women. Results: From March 2001 through October 2022, there were 54,372 women with VTE. During anticoagulation (median, 181 days), 318 (0.6%) developed abnormal UB (major bleeding = 88, clinically relevant non-major (CRNM) = 230). On multivariable analysis, women aged 70 kg, with uterine cancer, recent UB, anemia, estrogen-related VTE, or receiving rivaroxaban or apixaban were at increased risk for abnormal UB. Using the prognostic score, 42,273 women (78%) were at low-risk, 8,828 (16%) intermediate-, and 3,271 (6.1%) at high-risk for abnormal UB. Their rates of abnormal UB were: 0.28 (95%CI: 0.23–0.35), 1.32 (95%CI: 1.07–1.61) and 7.12 (95%CI: 5.98–8.41) bleeds per 100 patient-years, respectively. The c-statistic was 0.80 (95%CI: 0.77–0.83). The rates of major UB were: 0.06 (95%CI: 0.04–0.09), 0.43 (95%CI: 0.30–0.60) and 1.85 (95%CI: 1.31–2.53) per 100 patient-years, respectively (c-statistic: 0.84; 95%CI: 0.80–0.89). The rates of CRNM uterine bleeding were: 0.21 (95%CI: 0.17–0.26), 0.85 (95%CI: 0.65–1.08), and 5.02 (95%CI: 4.09–6.10) bleeds per 100 patient-years, respectively (c-statistic: 0.78; 95%CI: 0.75–0.82). Conclusions: Using 7 variables easily available at admission, we built a prognostic score that reliably identified women with VTE at increased risk for abnormal UB during anticoagulation.

In this study was correlate the effects of drying time and intermittence of paddy rice on the physical, physicochemical, and morphological quality of polished and brown rice using near-infrared spectroscopy, X-ray diffraction, and scanning electron microscopy. Rice grain batches from mechanized harvesting with moisture contents between 24 and 20% (w.b.) were immediately subjected to drying and intermittence (average temperature of the grain mass of 40 °C) for a time of 14 h (number of times that the product underwent the drying and intermittence processes). For each drying time, grain sampling was performed to evaluate the physical quality of paddy rice and the physicochemical and morphological quality of polished and brown rice. The accumulated drying time provided an increase in the temperature of the grain mass, altering the physicochemical and morphological quality of polished and brown rice. The intermittence process did not contribute for the quality of the polished rice.

Background: Insertable cardiac monitors (ICMs) are increasingly used for cardiac rhythm diagnosis with expanding indications. Little has been reported about their use and efficacy. Objective: The study sought to evaluate the clinical utility of a novel ICM (Biotronik BIOMONITOR III) including the time to diagnosis in unselected patients with different ICM indications. Methods: Patients from 2 prospective clinical studies were included to determine the diagnostic yield of the ICM. The primary endpoint was time to clinical diagnosis per implant indication or to the first change in atrial fibrillation (AF) therapy. Results: A total of 632 patients were included with a mean follow-up of 233 ± 168 days. Of 384 patients with (pre)syncope, 34.2% had a diagnosis at 1 year. The most frequent therapy was permanent pacemaker implantation. Of 133 patients with cryptogenic stroke, 16.6% had an AF diagnosis at 1 year, resulting in oral anticoagulation. Of 49 patients with an indication for AF monitoring, 41.0% had a relevant change in AF therapy based on ICM data at 1 year. Of 66 patients with other indications, 35.4% received a rhythm diagnosis at 1 year. Moreover, 6.5% of the cohort had additional diagnoses: 26 of 384 patients with syncope, 8 of 133 patients with cryptogenic stroke, and 7 of 49 patients with AF monitoring. Conclusion: In a large unselected patient population with heterogeneous ICM indications, the primary endpoint of rhythm diagnosis was achieved in ∼1 in 4, and additional clinically relevant findings was achieved in 6.5% of patients at short-term follow-up.

Summary: Parkinson’s disease (PD) is a neurological disorder characterized by motor dysfunction, dopaminergic neuron loss, and alpha-synuclein (αSyn) inclusions. Many PD risk factors are known, but those affecting disease progression are not. Lifestyle and microbial dysbiosis are candidates in this context. Diet-driven gut dysbiosis and reduced barrier function may increase exposure of enteric neurons to toxins. Here, we study whether fiber deprivation and exposure to bacterial curli, a protein cross-seeding with αSyn, individually or together, exacerbate disease in the enteric and central nervous systems of a transgenic PD mouse model. We analyze the gut microbiome, motor behavior, and gastrointestinal and brain pathologies. We find that diet and bacterial curli alter the microbiome and exacerbate motor performance, as well as intestinal and brain pathologies, but to different extents. Our results shed important insights on how diet and microbiome-borne insults modulate PD progression via the gut-brain axis and have implications for lifestyle management of PD.

An experimental study of 256Rf spontaneous fission following the fusion reaction of 50Ti+208Pb was performed using the velocity filter SHELS of the Flerov laboratory at JINR. The average number of neutrons of ν‾=4.30±0.17 and variance of σν2=3.2 from the prompt neutron multiplicity distribution were obtained. The alpha decay branching ratio of bα=0.003−0.003+0.005 and the half-life of T1/2=(6.7±0.2) ms of the isotope were determined. For the first time, our neutron detector system allowed us to extend investigation of the prompt neutron multiplicity study to the superheavy element region.

Biomethane is a renewable natural gas substitute produced from biogas. Storage of this sustainable energy vector in confined clathrate hydrates, encapsulated in the pores of a host material, is a highly promising avenue to improve storage capacity and energy efficiency. Herein, a new type of periodic mesoporous organosilica (PMO) nanotubes, referred to as hollow ring PMO (HR-PMO), capable of promoting methane clathrate hydrate formation under mild working conditions (273 K, 3.5 MPa) and at high water loading (5.1 g water/g HR-PMO) is reported. Gravimetric uptake measurements reveal a steep single-stepped isotherm and a noticeably high methane storage capacity (0.55 g methane/g HR-PMO; 0.11 g methane/g water at 3.5 MPa). The large working capacity throughout consecutive pressure-induced clathrate hydrate formation-dissociation cycles demonstrates the material’s excellent recyclability (97% preservation of capacity). Supported by ex situ cryo-electron tomography and x-ray diffraction, HR-PMO nanotubes are hypothesized to promote clathrate hydrate nucleation and growth by distribution and confinement of water in the mesopores of their outer wall, along the central channels of the nanotubes and on the external nanotube surface. These findings showcase the potential for application of organosilica materials with hierarchical and interconnected pore systems for pressure-based storage of biomethane in confined clathrate hydrates.

Summary: The apolipoprotein E protein (apoE) confers differential risk for Alzheimer’s disease depending on which isoforms are expressed. Here, we present a 2-day immunoprecipitation protocol using the HJ15.4 monoclonal apoE antibody for the pull-down of native apoE particles. We describe major steps for apoE production via immortalized astrocyte culture and HJ15.4 antibody bead coupling for apoE particle pull-down, elution, and characterization. This protocol could be used to isolate native apoE particles from multiple model systems or human biospecimens. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: Background: The optimal timing for SARS-CoV-2 vaccines within the first year after allogeneic hematopoietic cell transplant (HCT) is poorly understood. Methods: We conducted a prospective, multicentre, observational study of allogeneic HCT recipients who initiated SARS-CoV-2 vaccinations within 12 months of HCT. Participants were enrolled at 22 academic cancer centers across the United States. Participants of any age who were planning to receive a first post-HCT SARS-CoV-2 vaccine within 12 months of HCT were eligible. We obtained blood prior to and after each vaccine dose for up to four vaccine doses, with an end-of-study sample seven to nine months after enrollment. We tested for SARS-CoV-2 spike protein (anti-S) IgG; nucleocapsid protein (anti-N) IgG; neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains; and SARS-CoV-2-specific T-cell receptors (TCRs). The primary outcome was a comparison of anti-S IgG titers at the post-V2 time point in participants initiating vaccinations

Purpose: Acute appendicitis is a common abdominal emergency worldwide. This study aimed at characterizing environmental risk factors influencing the development and severity of acute appendicitis. Methods: Patients from a Belgian acute appendicitis cohort (n = 374) and healthy controls from the 500 functional genomics (500FG) cohort (n = 513) were compared. Individuals with a history of appendectomy (n = 1067) and without a history of appendectomy (n = 8656) were available from the Nijmegen Biomedical Study (NBS). Questionnaires on demographics, lifestyle and environment were available. Binary logistic regression was used for prediction models. Results: Fifteen risk factors for developing acute appendicitis were identified. Binary logistic regression showed that 7 were independent risk factors: family history of acute appendicitis, having grown up in a rural environment, having a lower education, probiotic use as well as antibiotic use increased the risk of developing appendicitis. Fruit and fiber-rich vegetable consumption decreased the risk. Findings on vegetable consumption, smoking and level of education were replicated in the NBS population. Independent risk factors for complicated appendicitis were being male, higher age, and a delay to diagnosis of more than 48 h. Conclusions: Environmental exposures influence the risk of developing appendicitis. Further research into these factors is needed.

A sustainable diet is widely recognized as an effective way to solve environmental and healthy dilemmas. Due to economy improvement, food consumption is undergoing a dietary transition toward more animal-based products. However, very few studies explored how geographical locations are correlated with dietary environmental footprints. Here, we quantified the per capita ecological footprint (EFP) and Greenhouse gas (GHG) emissions of Chinese people’s food consumption during the 2015 to 2020 period. Our results showed that the southern residents with high per capita disposable income (PCDI) showed the highest EFP (0.596 ha) and GHG emissions (1946 kgCO2eq), and the northern residents with low PCDI showed the lowest EFP (0.368 ha) and GHG emissions (1260 kgCO2eq). The overconsumption of meat is severe in China, and southern high PCDI residents annually consumed 116.7% more than they need. The EFP and GHG emissions were significantly related to geographical locations (i.e., southern and northern areas), direct economic indicators (i.e., PCDI and food expenditure), and indirect economic indicators (i.e., urban and rural status, and East-Central-West areas) (all p

Cattle behaviour is fundamentally linked to the cows’ health, (re)production, and welfare. The aim of this study was to present an efficient method to incorporate Ultra-Wideband (UWB) indoor location and accelerometer data for improved cattle behaviour monitoring systems. In total, 30 dairy cows were fitted with UWB Pozyx wearable tracking tags (Pozyx, Ghent, Belgium) on the upper (dorsal) side of the cow’s neck. In addition to the location data, the Pozyx tag reports accelerometer data as well. The combination of both sensor data was performed in two steps. In the first step, the actual time spent in the different barn areas was calculated using location data. In the second step, accelerometer data were used to classify cow behaviour using the location information of step 1 (e.g., a cow located in the cubicles cannot be classified as feeding, or drinking). A total of 156 hours of video recordings were used for the validation. For each hour of data, the total time each cow spent in each area and performing which behaviours (feeding, drinking, ruminating, resting, and eating concentrates) were computed using the sensors and compared against annotated video recordings. Bland-Altman plots for the correlation and difference between the sensors and the video recording were then computed for the performance analysis. The overall performance of locating the animals into the correct functional areas was very high. The R2 was 0.99 (P

Despite a lot of research about predictive maintenance for onshore and offshore windmill farms, nearly no investigation has been performed to obtain the optimal sequence in which windmills are to be served in a predefined time frame. The higher fuel costs and the increasing time pressure on maintenance jobs urge the need for optimisation, so offshore windmills can be serviced at minimal costs and within a limited time frame. To minimise distance travelled, fuel consumption and average tardiness of all maintenance tasks to be carried out, a multi-objective, non-dominated sorting island model of genetic algorithms is used.The following novel contributions are realised: (i) A multi-objective island model is used, where on each island a different genetic algorithm is used to minimise a separate cost function per island. (ii) A set of non-dominated maintenance sequences, shown as a Pareto plane, are computed and (iii) these optimal solutions can be used by the planner to select the route to be followed by the CTV when travelling from windmill to windmill during a maintenance sequence.Tests on two of the islands have resulted in a relative improvement of around 65 to 70% on fuel consumption and distance in relation to a random sequence, while the third island has generated a relative gain of 69% in average weighed tardiness. The three islands combined have resulted in a set of Pareto optimal sequences for offshore windmill maintenance.

Hippocampal subfields (HCsf) are brain regions important for memory function that are vulnerable to decline with amnestic mild cognitive impairment (aMCI), which is often a preclinical stage of Alzheimer’s disease. Studies in aMCI patients often assess HCsf tissue integrity using measures of volume, which has little specificity to microstructure and pathology. We use magnetic resonance elastography (MRE) to examine the viscoelastic mechanical properties of HCsf tissue, which is related to structural integrity, and sensitively detect differences in older adults with aMCI compared to an age-matched control group. Group comparisons revealed HCsf viscoelasticity is differentially affected in aMCI, with CA1-CA2 and DG-CA3 exhibiting lower stiffness and CA1-CA2 exhibiting higher damping ratio, both indicating poorer tissue integrity in aMCI. Including HCsf stiffness in a logistic regression improves classification of aMCI beyond measures of volume alone. Additionally, lower DG-CA3 stiffness predicted aMCI status regardless of DG-CA3 volume. These findings showcase the benefit of using MRE in detecting subtle pathological tissue changes in individuals with aMCI via the HCsf particularly affected in the disease.

Background: Arteriovenous malformation (AVM) of the spinal cord are rare entities, with the dural AV-fistel the most common and well-studied form. Paraspinal AVM is an extremely rare condition, with their nidus lying exclusively extradural. Although most cases present as spontaneous epidural hemorrhage with acute onset of symptoms due to spinal cord compression, unruptured paraspinal AVMs may be asymptomatic or present with progressive neurological decline due to either medullary compression by ectatic epidural veins, medullary ischemia due to venous congestion, or a combination of both. Observation: In this article we report a case of an intraosseous AVM of the thoracic spine with epidural extension, mimicking a neoplastic lesion compressing the spinal cord, causing progressive paraparesis. The patient underwent prompt surgical decompression and resection via laminectomy. The peri and postoperative course were uneventful, and there was complete neurological recovery. Conclusion: Paraspinal AVMs may present as solid tumors, compressing the spinal cord. The aim of this article was to increase awareness of this rare entity in the differential diagnosis of spinal tumors, attributing to patient’s standard of care and safety. Post-treatment functional prognosis seems good, especially in comparison with an intradural/intramedullary allocation, but delayed diagnosis and treatment may leave the patient with residual neurological deficit.

Summary: Background: Better understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management. Methods: Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed. Findings: The median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering of ordinal score over time revealed distinct disease course trajectories. Risk factors associated with prolonged hospitalization or death by day 28 included age ≥ 65 years (odds ratio [OR], 2.01; 95% CI 1.28–3.17), Hispanic ethnicity (OR, 1.71; 95% CI 1.13–2.57), elevated baseline creatinine (OR 2.80; 95% CI 1.63– 4.80) or troponin (OR 1.89; 95% 1.03–3.47), baseline lymphopenia (OR 2.19; 95% CI 1.61–2.97), presence of infiltrate by chest imaging (OR 3.16; 95% CI 1.96–5.10), and high SARS-CoV2 viral load (OR 1.53; 95% CI 1.17–2.00). Fatal cases had the lowest ratio of SARS-CoV-2 antibody to viral load levels compared to other trajectories over time (p=0.001). 589 survivors (51%) completed at least one survey at follow-up with 305 (52%) having at least one symptom consistent with PASC, most commonly dyspnea (56% among symptomatic patients). Female sex was the only associated risk factor for PASC. Interpretation: Integration of PCR cycle threshold, and antibody values with demographics, comorbidities, and laboratory/radiographic findings identified risk factors for 28-day outcome severity, though only female sex was associated with PASC. Longitudinal clinical phenotyping offers important insights, and provides a framework for immunophenotyping for acute and long COVID-19. Funding: NIH.

Background: Real-time polymerase chain reaction (RT-PCR) testing on a nasopharyngeal swab is the current standard for SARS-CoV-2 virus detection. Since collection of this sample type is experienced uncomfortable by patients, saliva- and oropharyngeal swab collections should be considered as alternative specimens. Objectives: Evaluation of the relative performance of oropharyngeal swab, nasopharyngeal swab and saliva for the RT-PCR based SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variant detection. Study design: Nasopharyngeal swab, oropharyngeal swab and saliva were collected from 246 adult patients who presented for SARS-CoV-2 testing at the screening centre in Ypres (Belgium). RT-PCR SARS-CoV-2 detection was performed on all three sample types separately. Variant type was determined for each positive patient using whole genome sequencing or Allplex SARS-CoV-2 variants I and II Assay. Results and conclusions: Saliva is superior compared to nasopharyngeal swab for the detection of the Omicron variant. For the detection of the Delta variant, nasopharyngeal swab and saliva can be considered equivalent specimens. Oropharyngeal swab is the least sensitive sample type and shows little added value when collected in addition to a single nasopharyngeal swab.

Summary: Here, we present a robust protocol for the facile and rapid synthesis of functionalized secondary amines in continuous flow. More specifically, we describe a detailed guide to perform a photocatalyzed Petasis reaction within 50 min using alkyl boronic acid as radical precursor and a Vapourtec E-series as key equipment. The desired functionalized amine has been synthesized in mmol scale and with a productivity rate of 0.2 mmol/h. The protocol is limited to alkyl boronic acids.For complete details on the generation and use of this protocol, please refer to Oliva et al. (2021).

Abstract Background Venous thromboembolism (VTE) frequently occurs in hospitalized patients with coronavirus disease 2019 (COVID‐19). The optimal dose of anticoagulation for thromboprophylaxis in COVID‐19 is unknown. Aims To report VTE incidence and bleeding before and after implementing a hospital‐wide intensified thromboprophylactic protocol in patients with COVID‐19. Methods On March 31, 2020, we implemented an intensified thromboprophylactic protocol consisting of 50 IU anti‐Xa low molecular weight heparin (LMWH)/kg once daily at the ward, twice daily at the intensive care unit (ICU). We included all patients hospitalized in a tertiary care hospital with symptomatic COVID‐19 between March 7 and July 1, 2020. The primary outcome was the incidence of symptomatic or subclinical VTE and major bleeding during admission. Routine ultrasound screening for VTE was performed whenever logistically possible. Results We included 412 patients, of which 116 were admitted to the ICU. Of 219 patients with standard a prophylactic dose of LMWH, 16 (7.3%) had VTE, 10 of which were symptomatic (4.6%). Of 193 patients with intensified thromboprophylaxis, there were no symptomatic VTE cases, three incidental deep venous thrombosis cases (1.6%), and one incidental pulmonary embolism (0.5%). The major bleeding rate was 1.2% in patients with intensified thromboprophylaxis and 7.7% when therapeutic anticoagulation was needed. Conclusion In hospitalized patients with COVID‐19, there were no additional symptomatic VTEs and a reduction in incidental deep vein thrombosis after implementing systematic thromboprophylaxis with weight‐adjusted prophylactic (ward) to intermediate (ICU), but not therapeutic dosed anticoagulation. This intensified thromboprophylaxis was associated with a lower risk of major bleeding compared with therapeutic dosed anticoagulation.

Abstract: Transfusion of donor-derived red blood cells (RBC) is the most common form of cellular therapy. Donor availability and the potential risk of alloimmunization and other transfusion-related complications may, however, limit the availability of transfusion units, especially for chronically transfused patients. In vitro cultured, customizable RBC would negate these concerns and further increase precision medicine. Large-scale, cost-effective production depends on optimization of culture conditions. We developed a defined medium and adapted our protocols to good manufacturing practice (GMP) culture requirements, which reproducibly provided pure erythroid cultures from peripheral blood mononuclear cells without prior CD34+ isolation, and a 3 × 107-fold increase in erythroblasts in 25 days (or from 100 million peripheral blood mononuclear cells, 2 to 4 mL packed red cells can be produced). Expanded erythroblast cultures could be differentiated to CD71dimCD235a+CD44+CD117−DRAQ5− RBC in 12 days. More than 90% of the cells enucleated and expressed adult hemoglobin as well as the correct blood group antigens. Deformability and oxygen-binding capacity of cultured RBC was comparable to in vivo reticulocytes. Daily RNA sampling during differentiation followed by RNA-sequencing provided a high-resolution map/resource of changes occurring during terminal erythropoiesis. The culture process was compatible with upscaling using a G-Rex bioreactor with a capacity of 1 L per reactor, allowing transition toward clinical studies and small-scale applications.

Abstract: Ring sideroblasts (RS) emerge as result of aberrant erythroid differentiation leading to excessive mitochondrial iron accumulation, a characteristic feature for myelodysplastic syndromes (MDS) with mutations in the spliceosome gene SF3B1. However, RS can also be observed in patients diagnosed with acute myeloid leukemia (AML). The objective of this study was to characterize RS in patients with AML. Clinically, RS-AML is enriched for ELN adverse risk (55%). In line with this finding, 35% of all cases had complex cytogenetic aberrancies, and TP53 was most recurrently mutated in this cohort (37%), followed by DNMT3A (26%), RUNX1 (25%), TET2 (20%), and ASXL1 (19%). In contrast to RS-MDS, the incidence of SF3B1 mutations was low (8%). Whole-exome sequencing and SNP array analysis on a subset of patients did not uncover a single genetic defect underlying the RS phenotype. Shared genetic defects between erythroblasts and total mononuclear cell fraction indicate common ancestry for the erythroid lineage and the myeloid blast cells in patients with RS-AML. RNA sequencing analysis on CD34+ AML cells revealed differential gene expression between RS-AML and non RS-AML cases, including genes involved in megakaryocyte and erythroid differentiation. Furthermore, several heme metabolism-related genes were found to be upregulated in RS- CD34+ AML cells, as was observed in SF3B1 mut MDS. These results demonstrate that although the genetic background of RS-AML differs from that of RS-MDS, they have certain downstream effector pathways in common.

A search for dark matter (DM) with mass in the sub-GeV region (0.32–1 GeV) was conducted by looking for an annual modulation signal in XMASS, a single-phase liquid xenon detector. Inelastic nuclear scattering accompanied by bremsstrahlung emission was used to search down to an electron equivalent energy of 1 keV. The data used had a live time of 2.8 years (3.5 years in calendar time), resulting in a total exposure of 2.38 ton-years. No significant modulation signal was observed and 90% confidence level upper limits of 1.6×10−33 cm2 at 0.5 GeV was set for the DM-nucleon cross section. This is the first experimental result of a search for DM mediated by the bremsstrahlung effect. In addition, a search for DM with mass in the multi-GeV region (4–20 GeV) was conducted with a lower energy threshold than previous analysis of XMASS. Elastic nuclear scattering was used to search down to a nuclear recoil equivalent energy of 2.3 keV, and upper limits of 2.9 ×10−42 cm2 at 8 GeV was obtained. Keywords: Sub-GeV dark matter, Annual modulation, Liquid xenon