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The most well-known benefits of heavy commercial vehicle (HCV) platooning include fuel savings and emission reductions. In addition, HCV platooning under SAE automation level 4 or 5 can mitigate the truck driver shortage in North America by eliminating the driver from one or more HCVs in a platoon. This study investigates the passing sight distance (PSD) required to overtake a truck platoon or long combination vehicle (LCV). The PSD is one of the most important highway geometric design parameters. This study modified the 2018 AASHTO's PSD model for HCV platooning and long combination vehicles (LCVs). A micro-simulation model is used to validate the outcomes of the modified AASHTO model. The estimated PSDs suggest that it may be possible to operate two-HCV platoons on two-lane highways that already allow LCV operation if appropriate passing lanes are installed. The study's approach and findings are expected to help transportation engineers and government agencies prioritize two-lane highway sections for possible HCV platooning operation.

The Weather Research and Forecasting (WRF) double-moment 6-class (WDM6) scheme was modified by incorporating predicted graupel density. Explicitly predicted graupel density, in turn, modifies graupel characteristics such as the fall velocity–diameter and mass–diameter relationships of graupel. The modified WDM6 has been evaluated based on a two-dimensional (2D) idealized squall line simulation and winter snowfall events that occurred during the International Collaborative Experiment for Pyeongchang Olympics and Paralympics (ICE-POP 2018) field campaign over the Korean Peninsula. From the 2D simulation, we confirmed that the modified WDM6 can simulate varying graupel densities, ranging from low values in an anvil cloud region to high values in the convective region at the mature stage of a squall line. Simulations with the modified WDM6 increased graupel amounts at the surface and decreased graupel aloft because of the faster sedimentation of graupel for two winter snowfall cases during the ICE-POP 2018 campaign, as simulated in the 2D idealized model. The altered graupel sedimentation in the modified WDM6 influenced the magnitude of the major microphysical processes of graupel and snow, subsequently reducing the surface snow amount and precipitation over the mountainous region. The reduced surface precipitation over the mountainous region mitigates the surface precipitation bias observed in the original WDM6, resulting in better statistical skill scores for the root mean square errors. Notably, the modified WDM6 reasonably captures the relationship between graupel density and its fall velocity, as retrieved from 2D video disdrometer measurements, thus emphasizing the necessity of including predicted graupel density to realistically represent the microphysical properties of graupel in models.

Abstract Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP–SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP–SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP–SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a hub SNP with a significant main effect and a large minor allele frequency (MAF) tended to have a higher false-positive rate. In addition, peripheral null SNPs in a cluster with a small MAF tended to enhance false positivity. We also demonstrated that using the modified significance criterion based on the 3 p-value rules and the bootstrap approach (3pRule + bootstrap) can reduce false positivity and maintain high true positivity. In addition, our results also showed that a pair without a significant main effect tends to have weak or no interaction. This study identified the cluster effect and suggested using the 3pRule + bootstrap approach to enhance SNP–SNP interaction detection accuracy.

Abstract Background Cambodia’s health sector faces significant challenges exacerbated by aid fragmentation, where development aid is dispersed among numerous small, uncoordinated projects. This study examines the distribution of health sector aid among Cambodia’s principal donors to identify priorities, overlaps, and potential collaboration opportunities, addressing the urgent need for aid efficiency and alignment with national health priorities. Methods Utilizing OECD datasets and the Herfindahl-Hirschman Index (HHI) for the years 2010–2021, this study quantifies aid fragmentation within Cambodia’s health sector. It analyzes aid allocations from the top five donors—United States, Australia, South Korea, Japan, and Germany—across various health projects and initiatives, evaluating the extent of fragmentation and identifying areas for potential donor collaboration. Results This study’s findings highlight a pervasive issue of aid fragmentation within Cambodia’s health sector, evident through the sector’s low HHI score. This indicates a widespread distribution of aid across numerous small-scale initiatives, rather than targeted, unified efforts. A notable example includes Japan and Korea, which exhibit lower HHI scores, indicating a more pronounced fragmentation in their aid allocation. These countries’ contributions are spread across various sectors without a dominant focus, contrasting with the United States’ significant dedication to infectious disease control. However, beyond this specific area, the US’s aid distribution across other priority health areas shows signs of fragmentation. This scattered approach to aid allocation, even amidst instances of focused support, illustrates the overarching challenge of aligning donor contributions with the holistic needs of Cambodia’s health infrastructure. Conclusions This investigation highlights the critical need for enhanced collaboration and strategic harmonization among international donors to mitigate aid fragmentation in Cambodia’s health sector. It underscores the importance of adopting integrated and priority-aligned aid strategies to improve the efficiency and impact of health aid. By fostering synergistic partnerships and harmonizing donor efforts, there is a potential to create a more cohesive support framework that resonates with Cambodia’s comprehensive health requirements and contributes to sustainable health outcomes. Such harmonization not only aligns with Sustainable Development Goal 3 by optimizing health services and outcomes but also strengthens global partnerships under Sustainable Development Goal 17, fostering a unified approach to international development.

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer with a high risk of recurrence and metastasis. Regular surveillance through physical exams and imaging studies is crucial for the timely detection of recurrences. MCC patients who produce antibodies to the Merkel cell polyomavirus oncoprotein may benefit from antibody testing in addition to routine imaging surveillance for the early detection of disease recurrence. The clinically available Anti MERKel cell panel (AMERK) is a sensitive tumor marker for Merkel cell polyomavirus positive MCC.Although AMERK is highly sensitive, imaging remains necessary to confirm the location of disease recurrence. MCC exhibits characteristic imaging features, making appropriate imaging modalities, and interpretation important for detection.We present 3 representative patient cases that highlight effective utilization of the AMERK test in addition to imaging for the early detection of MCC recurrence. The rise in the AMERK titer may occur before the disease reaches detectable size on computed tomography scans. Positron emission tomography (PET)-CT can serve as an alternative modality for the early detection of disease. Even subtle abnormalities in 18F-FDG uptake may be significant if accompanied by an increased AMERK titer. Alternative imaging modalities, such as 68Ga-DOTATATE PET-CT and magnetic resonance imaging, can be useful in revealing clinically occult disease in MCC patients.In summary, the AMERK antibody test, alongside imaging, enhances sensitivity in detecting recurrence. By combining these strategies of blood test and imaging, healthcare professionals can identify early signs of MCC recurrence, leading to prompt interventions and improved patient outcomes.

The incidence of spotted fever group (SFG) rickettsioses in the United States has tripled since 2010. Rocky Mountain spotted fever, the most severe SFG rickettsiosis, is caused by Rickettsia rickettsii. The lack of species-specific confirmatory testing obfuscates the relative contribution of R. rickettsii and other SFG Rickettsia to this increase. We report a newly recognized rickettsial pathogen, Rickettsia sp. CA6269, as the cause of severe Rocky Mountain spotted fever–like illness in 2 case-patients residing in northern California. Multilocus sequence typing supported the recognition of this pathogen as a novel Rickettsia genotype most closely related to R. rickettsii. Cross-reactivity observed for an established molecular diagnostic test indicated that Rickettsia sp. CA6269 might be misidentified as R. rickettsii. We developed a Rickettsia sp. CA6269–specific real-time PCR to help resolve this diagnostic challenge and better characterize the spectrum of clinical disease and ecologic epidemiology of this pathogen.

This paper presents a method for stereo visual odometry and mapping that integrates VINS-Fusion-based visual odometry estimation with deep learning techniques for camera pose tracking and stereo image matching. Traditional approaches in the VINS-Fusion relied on classical methods for feature extraction and matching, which often resulted in inaccuracies in triangulation-based 3D position estimation. These inaccuracies could be mitigated by incorporating IMU-based position estimation, which yielded more accurate odometry estimates compared to using stereo camera only in three-dimensional space. Consequently, the original VINS-stereo algorithm necessitated a tightly-coupled integration of IMU sensor measurements with estimated visual odometry.To address these challenges, our work proposes replacing the traditional feature extraction method used in VINS-Fusion, the Shi-Tomasi (Good Features to Track) technique, with feature extraction via the SuperPoint deep network. This approach has demonstrated promising experimental results. Additionally, we have applied deep learning models to the matching of feature points that project the same three-dimensional point to pixel coordinates in different images. Instead of using the KLT optical flow algorithm previously employed by VINS-Fusion, our proposed method utilizes SuperGlue, a deep graph neural network for graph matching, to improve image tracking and stereo image matching performance. The performance of the proposed algorithm is evaluated using the publicly available EuRoC dataset, providing a comparison with existing algorithms.

Abstract Cancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.

Background: To evaluate the association of right vs left single lung transplants (SLT) from split lung donors with long-term post-transplant recipient outcomes. Methods: We performed a retrospective review of the Scientific Registry of Transplant Recipients data of split SLT adult recipients comparing right and left lung grafts between 2005 and 2021. We used a paired donor model to account for underlying differences between donors and evaluated post-transplant patient and graft survival with Cox proportional hazard models with robust variance estimates adjusted for recipient characteristics. We also used Wilcoxon signed-rank, McNemar’s, and Bowker’s tests to evaluate complication rates between donor pairs. Results: There were 5,180 recipients with 2,590 right and left split allografts. Left SLT had higher rates of mortality (hazards ratio [HR] = 1.17, 95% confidence interval [CI]: 1.08, 1.27) and graft failure (HR = 1.16, 95% CI: 1.06, 1.26) compared to right SLT in adjusted models. There were more early deaths (5 days) (n = 319, 12.6% vs n = 270, 10.6%; p = 0.030). Conclusions: Left SLT was associated with significantly worse mortality and graft failure while right SLT was associated with more short-term complications from split lung donors. Organ listing and acceptance decisions should consider donor lung laterality.

Treatment with the hypomethylating agent 5-azacytidine (AZA) increases survival in high-risk (HR) myelodysplastic syndrome (MDS) patients, but predicting patient response and overall survival remains challenging. To address these issues, we analyzed mutational and transcriptional profiles in CD34+ hematopoietic stem/progenitor cells (HSPCs) before and following AZA therapy in MDS patients. AZA treatment led to a greater reduction in the mutational burden in both blast and hematological responders than non-responders. Blast and hematological responders showed transcriptional evidence of pre-treatment enrichment for pathways such as oxidative phosphorylation, MYC targets, and mTORC1 signaling. While blast non-response was associated with TNFa signaling and leukemia stem cell signature, hematological non-response was associated with cell-cycle related pathways. AZA induced similar transcriptional responses in MDS patients regardless of response type. Comparison of blast responders and non-responders to normal controls, allowed us to generate a transcriptional classifier that could predict AZA response and survival. This classifier outperformed a previously developed gene signature in a second MDS patient cohort, but signatures of hematological responses were unable to predict survival. Overall, these studies characterize the molecular consequences of AZA treatment in MDS HSPCs and identify a potential tool for predicting AZA therapy responses and overall survival prior to initiation of therapy.

Abstract Acute myeloid leukemia (AML) is a fatal malignancy of the blood and bone marrow. Leukemic stem cells (LSCs) are a rare subset of leukemic cells that promote the development and progression of AML, and eradication of LSCs is critical for effective control of this disease. Emetine is an FDA-approved antiparasitic drug with antitumor properties; however, little is known about its potential against LSCs. Herein, we explored the antileukemic potential of emetine, focusing on its effects on AML stem/progenitor cells. Emetine exhibited potent cytotoxic activity both in hematologic and solid cancer cells and induced AML cell differentiation. Emetine also inhibited AML stem/progenitor cells, as evidenced by decreased expression of CD34, CD97, CD99, and CD123 in KG-1a cells, indicating anti-AML stem/progenitor cell activities. The administration of emetine at a dosage of 10 mg/kg for two weeks showed no significant toxicity and significantly reduced xenograft leukemic growth in vivo. NF-κB activation was reduced in emetine-treated KG-1a cells, as shown by reduced phospho-NF-κB p65 (S529) and nuclear NF-κB p65. DNA fragmentation, YO-PRO-1 staining, mitochondrial depolarization and increased levels of active caspase-3 and cleaved PARP (Asp214) were detected in emetine-treated KG-1a cells. Moreover, treatment with the pancaspase inhibitor Z-VAD(OMe)-FMK partially prevented the apoptotic cell death induced by emetine. Emetine treatment also increased cellular and mitochondrial reactive oxygen species, and emetine-induced apoptosis in KG-1a cells was partially prevented by the antioxidant N-acetylcysteine, indicating that emetine induces apoptosis, at least in part, by inducing oxidative stress. Overall, these studies indicate that emetine is a novel potential anti-AML agent with promising activity against stem/progenitor cells, encouraging the development of further studies aimed at its clinical application.

ABSTRACTImmune checkpoint inhibitors (ICI) are increasingly used in combination. To understand the effects of different ICI categories, we characterized changes in circulating autoantibodies in patients enrolled in the E4412 trial (NCT01896999) of brentuximab vedotin (BV) plus ipilimumab, BV plus nivolumab, or BV plus ipilimumab-nivolumab for Hodgkin Lymphoma. Cycle 2 Day 1 (C2D1) autoantibody levels were compared to pre-treatment baseline. Across 112 autoantibodies tested, we generally observed increases in ipilimumab-containing regimens, with decreases noted in the nivolumab arm. Among 15 autoantibodies with significant changes at C2D1, all nivolumab cases exhibited decreases, with more than 90% of ipilimumab-exposed cases showing increases. Autoantibody profiles also showed differences according to immune-related adverse event (irAE) type, with rash generally featuring increases and liver toxicity demonstrating decreases. We conclude that dynamic autoantibody profiles may differ according to ICI category and irAE type. These findings may have relevance to clinical monitoring and irAE treatment.

Abstract Introduction Men with African ancestry have the highest incidence and mortality rates of prostate cancer (PCa) worldwide. Methods This study aimed to identify differentially methylated genes between tumor vs. adjacent normal and aggressive vs. indolent PCa in 121 African American patients. Epigenome‐wide DNA methylation patterns in tumor DNA were assessed using the human Illumina Methylation EPIC V1 array. Results Around 5,139 differentially methylated CpG‐sites (q 0.2) were identified when comparing normal vs. tumor, with an overall trend of hypermethylation in prostate tumors. Multiple representative differentially methylated regions (DMRs), including immune‐related genes, such as CD40, Galectin3, OX40L, and STING, were detected in prostate tumors when compared to adjacent normal tissues. Based on an epigenetic clock model, we observed that tumors’ total number of stem cell divisions and the stem cell division rate were significantly higher than adjacent normal tissues. Regarding PCa aggressiveness, 2,061 differentially methylated CpG‐sites (q .05) were identified when the grade group (GG)1 was compared with GG4/5. Among these 2,061 CpG sites, 155 probes were consistently significant in more than one comparison. Among these genes, several immune system genes, such as COL18A1, S100A2, ITGA4, HLA‐C, and ADCYAP1, have previously been linked to tumor progression in PCa. Conclusion Several differentially methylated genes involved in immune‐oncologic pathways associated with disease risk or aggressiveness were identified. In addition, 261 African American‐specific differentially methylated genes related to the risk of PCa were identified. These results can shedlight on potential mechanisms contributing to PCa disparities in the African American Population.

With a renewed focus on health equity in the United States driven by national crises and legislation to improve digital healthcare innovation, there is a need for the designers of digital health tools to take deliberate steps to design for equity in their work. A concrete toolkit of methods to design for health equity is needed to support digital health practitioners in this aim. This narrative review summarizes several health equity frameworks to help digital health practitioners conceptualize the equity dimensions of importance for their work, and then provides design approaches that accommodate an equity focus. Specifically, the Double Diamond Model, the IDEAS framework and toolkit, and community collaboration techniques such as participatory design are explored as mechanisms for practitioners to solicit input from members of underserved groups and better design digital health tools that serve their needs. Each of these design methods requires a deliberate effort by practitioners to infuse health equity into the approach. A series of case studies that use different methods to build in equity considerations are offered to provide examples of how this can be accomplished and demonstrate the range of applications available depending on resources, budget, product maturity, and other factors. We conclude with a call for shared rigor around designing digital health tools that deliver equitable outcomes for members of underserved populations.

Despite advances in screening, diagnosis, and treatment for prostate cancer (PCa), Black men tend to be diagnosed at younger ages, have higher mortality rates, and are at increased risk of recurrence or metastasis compared to their White counterparts. PCa disparities among Black men are caused by a complex interaction of social, behavioral, and biological factors across the public policy, community, organizational, interpersonal, and individual levels. Key contributing factors include mistrust in the health care system, poor communication between patients and providers, low awareness of screening guidelines, and high medical costs. These disparities are further exacerbated by the low representation of Black men in clinical trials, which limits access to high-quality cancer care and generalizability for PCa treatments. In this narrative review of the existing literature, we examined the epidemiology and identified contributing factors, and propose multi-level strategies to address and mitigate disparities among Black men with PCa.

Purpose A daily quality assurance (QA) check in proton therapy is ensuring that the range of each proton beam energy in water is accurate to 1 mm. This is important for ensuring that the tumor is adequately irradiated while minimizing damage to surrounding healthy tissue. It is also important to verify the total charge collected against the beam model. This work proposes a time-efficient method for verifying the range and total charge of proton beams at different energies using a multilayer Faraday collector (MLFC). Methods We used an MLFC-128-250 MeV comprising 128 layers of thin copper foils separated by thin insulating Kapton TM layers. Protons passing through the collector induce a charge on the metallic foils, which is integrated and measured by a multichannel electrometer. The charge deposition on the foils provides information about the beam range. Results Our results show that the proton beam range obtained using MLFC correlates closely with the range obtained from commissioning water tank measurements for all proton energies. Upon applying a range calibration factor, the maximum deviation is 0.4 g/cm 2 . The MLFC range showed no dependence on the number of monitor units and the source-to-surface distance. Range measurements collected over multiple weeks exhibited stability. The total charge collected agrees closely with the theoretical charge from the treatment planning system beam model for low- and mid-range energies. Conclusions We have calibrated and commissioned the use of the MLFC to easily verify range and total charge of proton beams. This tool will improve the workflow efficiency of the proton QA.

Merkel cell carcinoma (MCC) incidence has risen to approximately 3,000 cases annually in the USA. Although anti-programmed cell death (ligand) 1 (PD-(L)1) agents are now the first-line treatment for advanced MCC, approximately 50% of such patients do not persistently benefit. In PD-(L)1-refractory cases, ipilimumab (anti-cytotoxic T lymphocyte antigen-4) is often added; however, the extent of the clinical benefit of this combination is controversial. We identified one prospective study, three retrospective studies, and three case reports regarding this combination in refractory MCC. The aggregate response rate from retrospective studies was 32% (13 of 41 patients) with 4 complete responses (CR) and 9 partial responses (PR). In the prospective study, the response rate was very similar at 31% (8 of 26 patients; 4 CR, 4 PR). Response durability was highly variable (range 2 to >43 months), with patients achieving CR having greater durability. Immune-related adverse events (irAEs) were ≥grade III in 29% (retrospective cohort, N=41) and 36% (prospective cohort, N=50). While these aggregate data indicate adding ipilimumab should be considered in this setting, many patients with refractory MCC are ineligible due to comorbidities/irAEs, and approximately 70% will not benefit from this regimen. There is thus a significant unmet need in PD-(L)1-refractory MCC and clinical trials in this setting should be encouraged.

Objectives Long-term sickness absence from employment has negative consequences for the economy and can lead to widened health inequalities. Sick notes (also called ‘fit notes’) are issued by general practitioners when a person cannot work for health reasons for more than 7 days. We quantified the sick note rate in people with evidence of COVID-19 in 2020, 2021 and 2022, as an indication of the burden for people recovering from COVID-19.Design Cohort study.Setting With National Health Service (NHS) England approval, we used routine clinical data (primary care, hospital and COVID-19 testing records) within the OpenSAFELY-TPP database.Participants People 18–64 years with a recorded positive test or diagnosis of COVID-19 in 2020 (n=365 421), 2021 (n=1 206 555) or 2022 (n=1 321 313); general population matched in age, sex and region in 2019 (n=3 140 326), 2020 (n=3 439 534), 2021 (n=4 571 469) and 2022 (n=4 818 870); people hospitalised with pneumonia in 2019 (n=29 673).Primary outcome measure Receipt of a sick note in primary care.Results Among people with a positive SARS-CoV-2 test or COVID-19 diagnosis, the sick note rate was 4.88 per 100 person-months (95% CI 4.83 to 4.93) in 2020, 2.66 (95% CI 2.64 to 2.67) in 2021 and 1.73 (95% CI 1.72 to 1.73) in 2022. Compared with the age, sex and region-matched general population, the adjusted HR for receipt of a sick note over the entire follow-up period (up to 10 months) was 4.07 (95% CI 4.02 to 4.12) in 2020 decreasing to 1.57 (95% CI 1.56 to 1.58) in 2022. The HR was highest in the first 30 days postdiagnosis in all years. Among people hospitalised with COVID-19, after adjustment, the sick note rate was lower than in people hospitalised with pneumonia.Conclusions Given the under-recording of postacute COVID-19-related symptoms, these findings contribute a valuable perspective on the long-term effects of COVID-19. Despite likely underestimation of the sick note rate, sick notes were issued more frequently to people with COVID-19 compared with those without, even in an era when most people are vaccinated. Most sick notes occurred in the first 30 days postdiagnosis, but the increased risk several months postdiagnosis may provide further evidence of the long-term impact.

BackgroundObesity and rapid weight gain are established risk factors for noncommunicable diseases and have emerged as independent risk factors for severe disease following Coronavirus Disease 2019 (COVID-19) infection. Restrictions imposed to reduce COVID-19 transmission resulted in profound societal changes that impacted many health behaviours, including physical activity and nutrition, associated with rate of weight gain. We investigated which clinical and sociodemographic characteristics were associated with rapid weight gain and the greatest acceleration in rate of weight gain during the pandemic among adults registered with an English National Health Service (NHS) general practitioner (GP) during the COVID-19 pandemic.Methods and findingsWith the approval of NHS England, we used the OpenSAFELY platform inside TPP to conduct an observational cohort study of routinely collected electronic healthcare records. We investigated changes in body mass index (BMI) values recorded in English primary care between March 2015 and March 2022. We extracted data on 17,742,365 adults aged 18 to 90 years old (50.1% female, 76.1% white British) registered with an English primary care practice. We estimated individual rates of weight gain before (δ-prepandemic) and during (δ-pandemic) the pandemic and identified individuals with rapid weight gain (>0.5 kg/m2/year) in each period. We also estimated the change in rate of weight gain between the prepandemic and pandemic period (δ-change = δ-pandemic-δ-prepandemic) and defined extreme accelerators as the 10% of individuals with the greatest increase in their rate of weight gain (δ-change ≥1.84 kg/m2/year) between these periods. We estimated associations with these outcomes using multivariable logistic regression adjusted for age, sex, index of multiple deprivation (IMD), and ethnicity. P-values were generated in regression models. The median BMI of our study population was 27.8 kg/m2, interquartile range (IQR) [24.3, 32.1] in 2019 (March 2019 to February 2020) and 28.0 kg/m2, IQR [24.4, 32.6] in 2021. Rapid pandemic weight gain was associated with sex, age, and IMD. Male sex (male versus female: adjusted odds ratio (aOR) 0.76, 95% confidence interval (95% CI) [0.76, 0.76], p < 0.001), older age (e.g., 50 to 59 years versus 18 to 29 years: aOR 0.60, 95% CI [0.60, 0.61], p < 0.001]); and living in less deprived areas (least-deprived-IMD-quintile versus most-deprived: aOR 0.77, 95% CI [0.77, 0.78] p < 0.001) reduced the odds of rapid weight gain. Compared to white British individuals, all other ethnicities had lower odds of rapid pandemic weight gain (e.g., Indian versus white British: aOR 0.69, 95% CI [0.68, 0.70], p < 0.001). Long-term conditions (LTCs) increased the odds, with mental health conditions having the greatest effect (e.g., depression (aOR 1.18, 95% CI [1.17, 1.18], p < 0.001)). Similar characteristics increased odds of extreme acceleration in the rate of weight gain between the prepandemic and pandemic periods. However, changes in healthcare activity during the pandemic may have introduced new bias to the data.ConclusionsWe found female sex, younger age, deprivation, white British ethnicity, and mental health conditions were associated with rapid pandemic weight gain and extreme acceleration in rate of weight gain between the prepandemic and pandemic periods. Our findings highlight the need to incorporate sociodemographic, physical, and mental health characteristics when formulating research, policies, and interventions targeting BMI in the period of post pandemic service restoration and in future pandemic planning.

The AMoRE-II experiment will search for the 0νββ decay of 100Mo nuclei using molybdate crystal scintillators, operating at milli-Kelvin (mK) temperatures, with a total of 80 kg of 100Mo. The background goal for the experiment is 10–4 counts/keV/kg/year in the region of interest around the 0νββ decay Q-value of 3,034 keV. To achieve this level, the rate of background signals arising from emissions produced by decays of radioactive impurities in the detector and shielding materials must be strictly controlled. To do this, concentrations of such impurities are measured and are controlled through materials selection and purification. In this paper, we describe the design and the construction materials used to build the AMoRE-II detector and shielding system, including active and passive shielding, the cryostat, and the detector holders and instrumentation, and we report on measurements of radioactive impurities within candidate and selected materials.

Objective: To explore the feasibility, acceptability, engagement, and impact of a virtual reality (VR) mindfulness program for students, residents, and fellows at a university medical campus. Patients and Methods: A total of 30 participants consented to participate in the study from September 13, 2021 to November 12, 2022. They completed a baseline assessment and were trained to use a VR headset to access mindfulness content. Participants were instructed to use the VR mindfulness program 3-5 times per week, or as often as they found helpful, and they completed midline and endline assessments and a semistructured interview about their experience with VR mindfulness. Results: Participant engagement in VR mindfulness ranged from 0 to 29 times over 8 weeks. Restricted free time, low portability, and privacy were identified as barriers to use. Participants reported positive experiences with VR mindfulness, especially with the gamified nature of the content. They also reported a desire for increased customization options. Participants’ stress scores decreased, and their mindful awareness and self-compassion scores increased. Conclusion: Overall findings support evidence of the feasibility and acceptability of VR mindfulness for college students on a medical campus. Short sessions and variable content may maximize sustained engagement. Implementation efforts should support participant engagement by including training and technological support. Future research should replicate study methods with the addition of a comparison group and should focus on evaluating the efficacy of VR mindfulness in the college student population.

In remote sensing, disparity calculation using stereo images is a very necessary task and provides information for estimating the terrain elevation. The fields using disparity of stereo satellite images are used in various fields such as terrain models, autonomous driving using 3D maps, and content development. However, extracting disparity from stereo satellite images is a very difficult task, and inaccurate disparity may be extracted due to complex environments, façade areas of buildings, and texture-less areas. Our proposed method improves feature extraction and 3D aggregation steps based on Gwc-Net using stereo images rectified through RPC (Rational Polynomial Coefficients). To this achieve, we first improve the accuracy of the initial cost volume by extracting important features using the attention module 2D CBAM. In addition, in the aggregation step, we use 3D CBAM to extract important features from the cost volume and use GCE (Correlate-and-Excite) to guide image features to the cost volume to improve disparity. To evaluate the proposed method, the accuracy of disparity is evaluated using RPC-corrected stereo satellite images of DFC2019 data track2 of the US3D dataset. As a result of the experiment, the proposed method exhibited improvement compared to the baseline Gwc-Net.

In this paper, we propose a method for performing 3D reconstruction by generating virtual RPC parameters from multi-view satellite stereo images provided by Google Earth (GE) software. In the multi-view stereo (MVS) image in a general case, after the pose and parameters of the camera are estimated, a dense 3D surface can be reconstructed. However, in the case of satellite images, it is not easy to obtain the original images with pose parameters of an area of interest. In the case of GE software, which can obtain images across the globe, the images provided are georeferenced and modified to fit the ground control point (GCP), so there is no camera model to explain the projection relationship. Therefore, the purpose of the proposed method is to perform 3D reconstruction by generating virtual camera parameters in modified satellite images obtained from GE software. In the proposed method, satellite images obtained from GE are estimated to be pinhole images using structure from motion (SfM) for initial reconstruction. After initial reconstruction, the 3D model is transformed from a distorted hexahedral space formed along a pixel ray to a UTM coordinate system metric space through a 3D homography-based georeferencing. A virtual rational polynomial camera (RPC) parameter is calculated through the satellite images and the 3D interspace correspondence point of UTM coordinates. The result is generated by virtual RPC and the MVS method using the RPC model. The reconstructed DSM using virtual RPC is improved over the initial reconstruction of the proposed process, and error measurement in the area with GT obtained significant results with an average of 1.366m on an MAE method.

This paper presents a method of visual LiDAR odometry and forest mapping, leveraging tree trunk detection and LiDAR localization techniques. In environments like dense forests, where smooth GPS signals are unreliable, we employ camera and LiDAR sensors to accurately estimate the robot's position. However, forested or orchard settings introduce unique challenges, including a diverse mixture of trees, tall grass, and uneven terrain. To address these complexities, we propose a distance-based filtering method to extract data composed solely of tree trunk information from 2D LiDAR. By restoring arc data from the LiDAR sensor to its circular shape, we obtain position and radius measurements of reference trees in the LiDAR coordinate system. Then, these values are stored in a comprehensive tree trunk database. Our approach combines visual-based SLAM and LiDAR-based SLAM independently, followed by an integration step using the Extended Kalman Filter (EKF) to improve odometry estimation. Utilizing the obtained odometry information and the EKF, we generate a tree map based on observed trees. In addition, we use the tree position in the map as the landmark to reduce the localization error in the proposed SLAM algorithm. Experimental results show that the loop-closing error ranges between 0.3 to 0.5 meters. In the future, it is expected that this method will also be applicable in the fields of path planning and navigation.

Introduction Accordingly, the Korean Medication Algorithm Project for Bipolar Disorder (KMAP-BP) working committee, composed of domestic experts, developed Korea’s first KMAP-BP in 2002 and later in 2006, 2010, and 2010. A revised version of KMAP-BP was announced every four years four times in 2014 and 2018.6-10). The treatment strategy considering the safety and tolerability of KMAP-BP 2022 was developed by collecting opinions from domestic bipolar disorder experts. Objectives Safety and tolerability of drugs are very important factors in the treatment of bipolar disorder. An expert opinion survey was conducted on treatment strategies in various special clinical situations, such as significant weight gain, characteristic drug side effects, low drug adherence, pregnant and reproductive women, and genetic counseling. Methods A written survey about treatment strategies related to safety and tolerability was prepared and focused on significant weight gain, characteristic drug side effects, low drug adherence, pregnant and reproductive women, and genetic counseling. Ninety-three experts of the review committee completed the survey. Results In the case of weight gain occurring during drug treatment, it was preferred to replace it with a drug that caused less weight gain, such as lamotrigine, aripiprazole, or ziprasidone. If there was a significant weight gain due to the treatment drug, it was preferred to intervene as soon as possible. In the case of hyperprolactinemia, it was selected to change the medication and discontinue it for benign rash caused by lamotrigine. In improving drug adherence, the preference for long-acting injections increased. Antipsychotics can be used with great caution in pregnant or reproductive women. Conclusions Treatment strategies in various clinical situations related to safety and tolerability in drug treatment for bipolar disorder were described. It is hoped that it will be useful in practical clinical situations. Disclosure of Interest None Declared

With the growing demand for robots in the industrial field, robot-related technologies with various functions have been introduced. One notable development is the implementation of robots that operate in collaboration with human workers to share tasks, without the need of any physical barriers such as safety fences. The realization of such collaborative operations in practice necessitates the assurance of safety if humans and robots collide. Thus, it is important to establish criteria for such collision scenarios to ensure robot safety and prevent injuries. Collision safety must be ensured in both pinching (quasi-static contact) and impact (transient contact) situations. To this end, we measured the force pain thresholds associated with impacts and evaluated the biomechanical limitations. This measurements were obtained through clinical trials involving physical collisions between human subjects and a device designed for generating impacts, and the force pain thresholds associated with transient collisions between humans and robots were analyzed. Specifically, the force pain threshold was measured at two different locations on the bodies of 37 adults aged 19–32 years, using two impactors with different shapes. The force pain threshold was compared with the results of other relevant studies. The results can help identify biomechanical limitations in a precise and reliable manner to ensure the safety of robots in collaborative applications.

Siloxanes are composed of silicon, oxygen, and alkyl groups and are emitted from consumer chemicals. Despite being entirely anthropogenic, siloxanes are being detected in remote regions and are ubiquitous in indoor and urban environments. Decamethylcyclopentasiloxane (D5) is one of the most common cyclic congeners, and smog chamber and oxidation flow reactor (OFR) experiments have found D5 + OH to form secondary organosiloxane aerosol (SOSiA). However, there is uncertainty about the reaction products and the reported SOSiA mass yields (YSOSiA) appear inconsistent. To quantify small volatile oxidation products (VOPs) and to consolidate the YSOSiA in the literature, we performed experiments using a potential aerosol mass OFR while varying D5 concentration, humidity, and OH exposure (OHexp). We use a proton transfer reaction time-of-flight mass spectrometer to quantify D5, HCHO, and HCOOH and to detect other VOPs, which we tentatively identify as siloxanols and siloxanyl formates. We determine molar yields of HCHO and HCOOH between 52 %–211 % and 45 %–127 %, respectively. With particle size distributions measured with a scanning mobility particle sizer, we find YSOSiA to be < 10 % at OHexp < 1.3 × 1011 s cm−3 and ∼ 20 % at OHexp, corresponding to that of the lifetime of D5 at atmospheric OH concentrations. We also find that YSOSiA is dependent on both organic aerosol mass loading and OHexp. We use a kinetic box model of SOSiA formation and oxidative aging to explain the YSOSiA values found in this study and the literature. The model uses a volatility basis set (VBS) of the primary oxidation products as well as an aging rate coefficient in the gas phase, kage,gas, of 2.2×10-12 cm3 s−1 and an effective aging rate coefficient in the particle phase, kage,particle, of 2.0 × 10−12 cm3 s−1. The combination of a primary VBS and OH-dependent oxidative aging predicts SOSiA formation much better than a standard-VBS parameterization that does not consider aging (root mean square error = 42.6 vs. 96.5). In the model, multi-generational aging of SOSiA products occurred predominantly in the particle phase. The need for an aging-dependent parameterization to accurately model SOSiA formation shows that concepts developed for secondary organic aerosol precursors, which can form low-volatile products at low OHexp, do not necessarily apply to D5 + OH. The resulting yields of HCHO and HCOOH and the parameterization of YSOSiA may be used in larger-scale models to assess the implications of siloxanes for air quality.

Several studies have reported an increasing trend of surface ozone in South Korea over the past few decades, using different measurement metrics. In this study, we examined the surface ozone trends in South Korea by analyzing the hourly or daily maximum 8 h average ozone concentrations (MDA8) measured at the surface from 2001 to 2021. We studied the diurnal, seasonal, and multi-decadal variations of these parameters at city, province, and background sites. We found that the fourth-highest MDA8 values exhibited positive trends in seven cities, nine provinces, and two background sites from 2001 to 2021. For the majority of sites, there was an annual increase of approximately 1–2 ppb. After early 2010, all sites consistently recorded MDA8 values exceeding 70 ppb, despite reductions in precursor pollutants such as NO2 and CO. The diurnal and seasonal characteristics of ozone exceedances, defined as the percentage of data points with hourly ozone concentrations exceeding 70 ppb, differed between the Seoul Metropolitan Area (SMA) and the background sites. In the SMA, the exceedances were more prevalent during summer compared to spring, whereas the background sites experienced higher exceedances in spring than in summer. This indicates the efficient local production of ozone in the SMA during summer and the strong influence of long-range transport during spring. The rest of the sites showed similar exceedance patterns during both spring and summer. The peak exceedances occurred around 16:00–17:00 in the SMA and most locations, while the background sites primarily recorded exceedances throughout the night. During the spring of the COVID-19 pandemic (2020–2021), ozone exceedances decreased at most locations, potentially due to significant reductions in NOx emissions in South Korea and China compared to the period of 2010–2019. The largest decreases in exceedances were observed at the background sites during spring. For instance, in Gosung, Gangwondo (approximately 600 m above sea level), the exceedances dropped from 30 % to around 5 % during the COVID-19 pandemic. Regional model simulations confirmed the concept of decreased ozone levels in the boundary layer in Seoul and Gangwon-do in response to emission reductions. However, these reductions in ozone exceedances were not observed in major cities and provinces during the summer of the COVID-19 pandemic, as the decreases in NOx emissions in South Korea and China were much smaller compared to spring. This study highlights the distinctions between spring and summer in the formation and transport of surface ozone in South Korea, emphasizing the importance of monitoring and modeling specific processes for each season or finer timescales.

Abstract Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

Background: Whether laparoscopic approach to gastrectomy for gastric cancer (GC) reduces the risk of pneumonia remains unknown. In this study, we compared pneumonia outcomes for patients with GC who underwent either laparoscopic gastrectomy (LG) or open gastrectomy (OG). Methods: The ACS NSQIP database was queried to identify patients with GC who underwent LG or OG between Jan 2012 - Dec 2018. Outcomes were compared using regression models. A post-hoc analysis was performed for elderly patients. Results: The study cohort included 2661 patients, 23.4 % undergoing LG. Laparoscopic approach lowered pneumonia risk (OR 0.47, p = .028) and reduced hospital length of stay, (5.3 vs 7.1 days, p < .001). Elderly patients undergoing LG demonstrated similar benefits. Risk factors for pneumonia included advanced age, dyspnea and weight-loss, whereas laparoscopic approach reduced this risk. Conclusions: LG in patients with GC has both statistically and clinically significant advantages over OG with respect to pneumonia. Further studies are needed to validate the relationship between postoperative pneumonia and surgical approach for gastrectomy.

Abstract Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on these widely used in vitro models of human and mouse adipogenesis, and on cell-to-cell variability during this process.

Abstract Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet. ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017.

BackgroundGeneration Z (Gen Z) includes individuals born between 1995 and 2012. These individuals experience high rates of anxiety and depression. Most Gen Z individuals identify with being spiritual, and aspects from religion and spirituality can be integrated into mental health treatment and care as both are related to lower levels of depression. However, research on the spiritual and mental health of Gen Z is sparse. To date, there are no systematic or scoping reviews on digital methods to address the spiritual and mental health of Gen Z. ObjectiveThis scoping review aimed to describe the current state of digital methods to address spiritual and mental health among Gen Z, identify the knowledge gaps, and make suggestions for how to leverage digital spiritual and mental health interventions for Gen Z. MethodsA comprehensive literature search was conducted in PubMed, Scopus, PsycInfo, CINAHL, Education Full Text, Google Scholar, SocIndex, and Sociological Abstracts. The inclusion criteria were as follows: (1) study population born between 1995 and 2012 (ie, Gen Z); (2) reporting on spiritual health or well-being, spirituality or religion, and mental health or well-being; (3) reporting on using digital methods; (4) publication in 1996 or beyond; (5) human subject research; (6) full text availability in English; (7) primary research study design; and (8) peer-reviewed article. Two authors screened articles and subsequently extracted data from the included articles to describe the available evidence. ResultsA total of 413 articles were screened at the title and abstract levels, of which 27 were further assessed with full text for eligibility. Five studies met the inclusion criteria, and data were extracted to summarize study characteristics and findings. The studies were performed across 4 different countries. There were 2 mixed-methods studies (South Africa and Canada), 2 cross-sectional studies (China and United States), and 1 randomized controlled trial (United States). Of these studies, only 2 discussed digital interventions (a text messaging–based intervention to improve spiritual and mental health, and a feasibility study for a mental health app). Other studies had a digital component with minor or unclear spiritual and mental health measures. Overall, there was a lack of consistency in how spiritual and mental health were measured. ConclusionsFew studies have focused on assessing the spiritual and mental health of Gen Z in the digital context, and no research to date has examined a digital spiritual and mental health application among Gen Z. Research is needed to inform the development and evaluation of approaches to address the spiritual and mental health of Gen Z via digital means (eg, mobile apps).

Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Purpose: A primary challenge in clinical genetics is accurate interpretation of identified variants and relaying the information to patients and providers. Inconsistencies around handling variant reclassifications and notifying patients, combined with the lack of prescriptive guidelines on re-evaluation, reanalysis, and return of variants, has created practice challenges. Although relevant empirical work has emerged, the scope and outcomes of this research have not been characterized. Methods: We conducted a systematic literature review of variant reclassification and recontact research (2013-2023) across subdisciplines of medical genetics. Of the 159 nonduplicate records screened, we summarize findings from 54 included research articles describing variant reclassification frequencies, outcomes, and stakeholder perspectives on recontact. Results: The included articles reported on active reclassification (n = 20), passive reclassification (n = 13), stakeholder surveys (n = 11), qualitative interviews (n = 7), and reanalysis of published or ClinVar data (n = 3). On average, active and passive approaches yielded different reclassification frequencies—31% and 20%, respectively, which were considerably higher than ClinVar (

Approximately 50% of Merkel cell carcinoma (MCC) patients facing this highly aggressive skin cancer initially respond positively to PD-1-based immunotherapy. Nevertheless, the recurrence of MCC post-immunotherapy emphasizes the pressing need for more effective treatments. Recent research has highlighted Cyclin-dependent kinases 4 and 6 (CDK4/6) as pivotal cell cycle regulators gaining prominence in cancer studies. This study reveals that the CDK4/6 inhibitor, palbociclib can enhance PD-L1 gene transcription and surface expression in MCC cells by activating HIF2α. Inhibiting HIF2α with TC-S7009 effectively counteracts palbociclib-induced PD-L1 transcription and significantly intensifies cell death in MCC. Simultaneously, co-targeting CDK4/6 and HIF2α boosts ROS levels while suppressing SLC7A11, a key regulator of cellular redox balance, promoting ferroptosis- a form of immunogenic cell death linked to iron. Considering the rising importance of immunogenic cell death in immunotherapy, this strategy holds promise for improving future MCC treatments, markedly increasing immunogenic cell death across various MCC cell lines, thus advancing cancer immunotherapy.

BackgroundGeneration Z and young millennials (ages 18-35 years), collectively referred to as GenZennials, are connected to technology and the internet like no other generation before them. This has mental health implications, such as increased rates of anxiety and stress. Recent research has shown that app-based mental health interventions can be useful to address such mental health concerns. However, spirituality is an untapped resource, especially since GenZennials largely identify as spiritual and already integrate spiritual practices into their self-care. ObjectiveThere were four objectives to this study: (1) comprehensively explore reasons why GenZennials use a spiritual self-care app (ie, Skylight; Radiant Foundation), (2) understand how GenZennials identify spiritually, (3) understand the app’s relevance to GenZennials, and (4) gather feedback and suggestions to improve the app. MethodsSemistructured interviews were conducted with 23 GenZennials (ages 18-35 years; mean 28.7, SD 5.0 years; n=20, 87% female) who used the Skylight app. Interviews were 30 to 60 minutes and conducted on Zoom. Thematic analysis was used to analyze interviews. ResultsFive major categories emerged from the analysis, each encompassing one to several themes: (1) reasons for using the Skylight app, (2) content favorites, (3) defining spiritual identity, (4) relevance to GenZennials, and (5) overall improvement recommendations. Participants used the app for various reasons including to relax, escape, or ground themselves; improve mood; and enhance overall health and wellness. Participants also cited the app’s variety of content offerings and its free accessibility as their primary reasons for using it. Most participants identified themselves as solely spiritual (8/23/35%) among the options provided (ie, spiritual or religious or both), and they appreciated the app’s inclusive content. Participants felt that the app was relevant to their generation as it offered modern content (eg, spiritual self-care activities and short content). Participants recommended adding more personalization capabilities, content, and representation to the app. ConclusionsThis is the first study to qualitatively explore GenZennials’ perspectives and the use of a spiritual self-care app. Our findings should inform the future creation and improvement of spiritual self-care apps aimed at cultivating GenZennials’ spiritual and mental well-being. Future research is warranted to examine the effects of using a spiritual self-care app on GenZennial mental health.

Abstract Background Inflammatory bowel disease is an inflammatory disorder that primarily impacts the gastrointestinal tract, leading to malnutrition and chronic microscopic intestinal blood loss. Uncontrolled systemic inflammation can impact other parts of the body, known as extraintestinal manifestations. Up to 25% of patients with inflammatory bowel disease are reported to have these complications in their skin, joints, bones, eyes, liver, lung, and pancreas (Rogler et al. in Gastroenterology 161(4):1118–1132, 2021). Neurologic involvement as extraintestinal manifestations are less common, reported at 3–19%, including neuropathies, demyelination, and cerebrovascular events (Morís in World J Gastroenterol. 20(5):1228–1237, 2014). Case presentation A 13-year-old Caucasian boy presented with 1 month of progressive lower-extremity pain, weakness, and weight loss. His physical examination was notable for cachexia, lower-extremity weakness, and chorea. Labs revealed normocytic anemia and systemic inflammation. Imaging revealed symmetric abnormal marrow signal in the pelvis and upper femurs. Pathologic examination of the bone revealed chronic inflammation consistent with chronic nonbacterial osteitis. Endoscopy revealed colonic inflammation consistent with inflammatory bowel disease. Conclusions Children and adolescents with musculoskeletal pain lasting more than 2 weeks with systemic signs or symptoms like weight loss should prompt evaluation for systemic inflammatory disorders such as chronic nonbacterial osteitis, which can occur in isolation or associated with inflammatory bowel disease. This patient also had a nonspecific neurologic abnormality, chorea, which resolved with treatment of underlying inflammatory disorder. These extraintestinal manifestations may be concurrent with or precede intestinal inflammation, requiring a high index of suspicion when investigating nonspecific systemic inflammation.

Abstract Background Previously, we isolated a riboflavin-overproducing Ashbya gossypii mutant (MT strain) and discovered some mutations in genes encoding flavoproteins. Here, we analyzed the riboflavin production in the MT strain, in view of flavoproteins, which are localized in the mitochondria. Results In the MT strain, mitochondrial membrane potential was decreased compared with that in the wild type (WT) strain, resulting in increased reactive oxygen species. Additionally, diphenyleneiodonium (DPI), a universal flavoprotein inhibitor, inhibited riboflavin production in the WT and MT strains at 50 µM, indicating that some flavoproteins may be involved in riboflavin production. The specific activities of NADH and succinate dehydrogenases were significantly reduced in the MT strain, but those of glutathione reductase and acetohydroxyacid synthase were increased by 4.9- and 25-fold, respectively. By contrast, the expression of AgGLR1 gene encoding glutathione reductase was increased by 32-fold in the MT strain. However, that of AgILV2 gene encoding the catalytic subunit of acetohydroxyacid synthase was increased by only 2.1-fold. These results suggest that in the MT strain, acetohydroxyacid synthase, which catalyzes the first reaction of branched-chain amino acid biosynthesis, is vital for riboflavin production. The addition of valine, which is a feedback inhibitor of acetohydroxyacid synthase, to a minimal medium inhibited the growth of the MT strain and its riboflavin production. In addition, the addition of branched-chain amino acids enhanced the growth and riboflavin production in the MT strain. Conclusion The significance of branched-chain amino acids for riboflavin production in A. gossypii is reported and this study opens a novel approach for the effective production of riboflavin in A. gossypii.

Infection with Borrelia miyamotoi in California, USA, has been suggested by serologic studies. We diagnosed B. miyamotoi infection in an immunocompromised man in California. Diagnosis was aided by plasma microbial cell–free DNA sequencing. We conclude that the infection was acquired in California.

Abstract Augmentation of anaplerosis, or replenishment of carbon lost during intermediary metabolic transitions, is desirable in energy metabolism defects. Triheptanoin, the triglyceride of 7-carbon heptanoic acid, is anaplerotic via direct oxidation or 5-carbon ketone body generation. In this context, triheptanoin can be used to treat Glucose transporter type 1 deficiency encephalopathy (G1D). An oral triheptanoin dose of 1 g/Kg/day supplies near 35% of the total caloric intake and impacted epilepsy and cognition in G1D. This provided the motivation to establish a maximum, potentially greater dose. Using a 3 + 3 dose-finding approach useful in oncology, we studied three age groups: 4–6, 6.8–10 and 11–16 years old. This allowed us to arrive at a maximum tolerated dose of 45% of daily caloric intake for each group. Safety was ascertained via analytical blood measures. One dose-limiting toxicity, occurring in 1 of 6 subjects, was encountered in the middle age group in the context of frequently reduced gastrointestinal tolerance for all groups. Ketonemia following triheptanoin was determined in another group of G1D subjects. In them, β-ketopentanoate and β-hydroxypentanoate concentrations were robustly but variably increased. These results enable the rigorous clinical investigation of triheptanoin in G1D by providing dosing and initial tolerability, safety and ketonemic potential. ClinicalTrials.gov registration: NCT03041363, first registration 02/02/2017.