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Abstract Quantitative imaging biomarkers (QIB) are increasingly used in clinical research to advance precision medicine approaches in oncology. Computed tomography (CT) is a modality of choice for cancer diagnosis, prognosis, and response assessment due to its reliability and global accessibility. Here, we contribute to the cancer imaging community through The Cancer Imaging Archive (TCIA) by providing investigator-initiated, same-day repeat CT scan images of 32 non–small cell lung cancer (NSCLC) patients, along with radiologist-annotated lesion contours as a reference standard. Each scan was reconstructed into 6 image settings using various combinations of three slice thicknesses (1.25 mm, 2.5 mm, 5 mm) and two reconstruction kernels (lung, standard; GE CT equipment), which spans a wide range of CT imaging reconstruction parameters commonly used in lung cancer clinical practice and clinical trials. This holds considerable value for advancing the development of robust Radiomics, Artificial Intelligence (AI) and machine learning (ML) methods.

Abstract Background Few implementation science (IS) measures have been evaluated for validity, reliability and utility – the latter referring to whether a measure captures meaningful aspects of implementation contexts. We present a real-world case study of rigorous measure development in IS that assesses Barriers and Facilitators in Implementation of Task-Sharing in Mental Health services (BeFITS-MH), with the objective of offering lessons-learned and a framework to enhance measurement utility. Methods We summarize conceptual and empirical work that informed the development of the BeFITS-MH measure, including a description of the Delphi process, detailed translation and local adaptation procedures, and concurrent pilot testing. As validity and reliability are key aspects of measure development, we also report on our process of assessing the measure’s construct validity and utility for the implementation outcomes of acceptability, appropriateness, and feasibility. Results Continuous stakeholder involvement and concurrent pilot testing resulted in several adaptations of the BeFITS-MH measure’s structure, scaling, and format to enhance contextual relevance and utility. Adaptations of broad terms such as “program,” “provider type,” and “type of service” were necessary due to the heterogeneous nature of interventions, type of task-sharing providers employed, and clients served across the three global sites. Item selection benefited from the iterative process, enabling identification of relevance of key aspects of identified barriers and facilitators, and what aspects were common across sites. Program implementers’ conceptions of utility regarding the measure’s acceptability, appropriateness, and feasibility clustered across several common categories. Conclusions This case study provides a rigorous, multi-step process for developing a pragmatic IS measure. The process and lessons learned will aid in the teaching, practice and research of IS measurement development. The importance of including experiences and knowledge from different types of stakeholders in different global settings was reinforced and resulted in a more globally useful measure while allowing for locally-relevant adaptation. To increase the relevance of the measure it is important to target actionable domains that predict markers of utility (e.g., successful uptake) per program implementers’ preferences. With this case study, we provide a detailed roadmap for others seeking to develop and validate IS measures that maximize local utility and impact.

Abstract Lenalidomide, bortezomib, and dexamethasone (RVd) have previously been established as standard-of-care induction therapy for newly diagnosed multiple myeloma (NDMM). More recently, randomized phase 3 data have demonstrated the benefit of the addition of daratumumab (Dara-RVd) to the RVd backbone in terms of improved both depth of response and long-term survival benefit as measured by progression-free survival (PFS). Our group has previously published on a historical cohort of 1000 NDMM patients uniformly treated with RVd induction with impressive both PFS and overall survival. Here, we present a comparative analysis of our RVd cohort with a recent cohort of 326 patients induced with Dara-RVd at our institution with intent to transplant. This analysis demonstrates the utility of this regimen in real-world clinical practice and provides additional insights into D-RVd performance in patient subsets often underrepresented in clinical trials, as well as the impact of daratumumab in maintenance for NDMM patients.

The Skaftafellsjökull is an outlet glacier in southern Iceland that has been retreating since 1890. While multiple studies have examined primary succession on the foreland of this glacier, no study has examined the distribution of woody biomass on the outwash plain. We investigated the distribution of one species, Betula pubescens, that grows on the foreland moraines and outwash plain of this glacier. The topography of the outwash plain is heterogeneous, consisting of broad bars of outwash gravel and boulders that are separated by narrow incised channels and broader swales. Vegetation on the outwash plain is primarily a moss–heath community. Birch are sparse on the outwash bar tops, but are more abundant and larger in the channels and swales between the bars. Although the area of the channels on the outwash plain is much less than that of the bar surfaces, the woody biomass of the outwash plain is dominated by the birch within these channels. Consequently, the mean woody biomass of the outwash plain exceeds that of the moraines. We propose that the microhabitat of the outwash plain channels provides a favorable environment for the growth of birch, primarily by providing a fine-grained substrate that promotes successful seeding and growth.

Abstract Mitochondria play a central role in cellular energy metabolism, and their dysfunction is increasingly recognized as a critical factor in the pathogenesis of diabetes-related cardiac pathophysiology, including vulnerability to ischemic events that culminate in myocardial infarction on the one hand and ventricular arrhythmias on the other. In diabetes, hyperglycemia and altered metabolic substrates lead to excessive production of reactive oxygen species (ROS) by mitochondria, initiating a cascade of oxidative stress that damages mitochondrial DNA, proteins, and lipids. This mitochondrial injury compromises the efficiency of oxidative phosphorylation, leading to impaired ATP production. The resulting energy deficit and oxidative damage contribute to functional abnormalities in cardiac cells, placing the heart at an increased risk of electromechanical dysfunction and irreversible cell death in response to ischemic insults. While cardiac mitochondria are often considered to be relatively autonomous entities in their capacity to produce energy and ROS, their highly dynamic nature within an elaborate network of closely-coupled organelles that occupies 30–40% of the cardiomyocyte volume is fundamental to their ability to exert intricate regulation over global cardiac function. In this article, we review evidence linking the dynamic properties of the mitochondrial network to overall cardiac function and its response to injury. We then highlight select studies linking mitochondrial ultrastructural alterations driven by changes in mitochondrial fission, fusion and mitophagy in promoting cardiac ischemic injury to the diabetic heart.

Abstract Background Little is known about how use of chemotherapy has evolved in breast cancer patients. We therefore describe chemotherapy patterns for women with stage I-IIIA breast cancer in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study using data from KPNC (Kaiser Permanente Northern California) and KPWA (Kaiser Permanente Washington). Findings Among 33,670 women, aged 18 + y, diagnosed with primary stage I-IIIA breast cancer at KPNC and KPWA from 2006 to 2019, we explored patterns of intravenous chemotherapy use, defined here as receipt of intravenous cytotoxic drugs and/or anti-HER2 therapies. We evaluated trends in chemotherapy receipt, duration over which chemotherapy was received, and number of associated infusion visits. In secondary analyses, we stratified by receipt of anti-HER2 therapies (trastuzumab and/or pertuzumab), given their longer duration. 38.9% received chemotherapy intravenously, declining from 40.2% in 2006 to 35.6% in 2019 (p-trend

Abstract Background Vesicular stomatitis virus (VSV), a vector-borne pathogen of livestock, emerges periodically in the western US. In New Mexico (NM), US, most cases occur close to the Rio Grande River, implicating black flies (Simulium spp.) as a possible vector. In 2020, VS cases were reported in NM from April to May, although total black fly abundance remained high until September. We investigated the hypothesis that transience of local VSV transmission results from transient abundance of key, competent black fly species. Additionally, we investigated whether irrigation canals in southern NM support a different community of black flies than the main river. Lastly, to gain insight into the source of local black flies, in 2023 we collected black fly larvae prior to the release of water into the Rio Grande River channel. Methods We randomly sub-sampled adult black flies collected along the Rio Grande during and after the 2020 VSV outbreak. We also collected black fly adults along the river in 2021 and 2022 and at southern NM farms and irrigation canals in 2022. Black fly larvae were collected from dams in the area in 2023. All collections were counted, and individual specimens were subjected to molecular barcoding for species identification. Results DNA barcoding of adult black flies detected four species in 2020: Simulium meridionale (N = 158), S. mediovittatum (N = 83), S. robynae (N = 26) and S. griseum/notatum (N = 1). Simulium robynae was only detected during the VSV outbreak period, S. meridionale showed higher relative abundance, but lower absolute abundance, during the outbreak than post-outbreak period, and S. mediovittatum was rare during the outbreak period but predominated later in the summer. In 2022, relative abundance of black fly species did not differ significantly between the Rio Grande sites and farm and irrigation canals. Intriguingly, 63 larval black flies comprised 56% Simulium vittatum, 43% S. argus and 1% S. encisoi species that were either extremely rare or not detected in previous adult collections. Conclusions Our results suggest that S. robynae and S. meridionale could be shaping patterns of VSV transmission in southern NM. Thus, field studies of the source of these species as well as vector competence studies are warranted. Graphical Abstract

Ultrasound images are often affected by limited resolution, artifacts, and inherent speckle noise. To address these challenges, researchers have explored denoising approaches. Recently, deep learning methods have demonstrated distinct advantages in ultrasound image denoising. However, further improvements are needed to preserve structural details, such as boundaries, edges, and margins. This paper proposes a hybrid CNN-transformer network called HCTSpeckle, an encoder-decoder network with a fusion block designed to enhance ultrasound images. The fusion block combines swin transformers to capture global modeling relationships, and convolutional neural networks to extract local modeling details. It is integrated into the encoder-decoder structure, allowing the model to focus on both local and global texture structural information. An improved swin block is also introduced into the network to improve robustness by extracting more significant features. HCTSpeckle was evaluated both quantitatively and qualitatively with clinical objectives using two public and two private datasets. Both results showed that HCTSpeckle significantly enhanced the ultrasound image quality and outperformed state-of-the-art methods in noise reduction and structure preservation across all four datasets. Compared to existing denoising methods, HCTSpeckle achieved notably faster performance in terms of complexity comparison, such as parameter counts, gigaFLOPs, and inference time. Moreover, this study assessed the effectiveness of HCTSpeckle for alveolar bone segmentation using dental images, demonstrating that HCTSpeckle significantly improved segmentation performance. Furthermore, an experienced radiologist blindly rated the 250 dental US images on a scale of 1 to 5, with 5 being the highest image quality, showing that HCTSpeckle consistently produced higher-quality images.

The precise alignment of 3D echocardiographic images taken from different views has been shown to enhance image quality and increase the field of view. This study proposes a novel sequential Monte Carlo (SMC) algorithm for the 3D-3D rigid registration of echocardiographic images with significant overlap that is robust to the noise present in ultrasound images. The algorithm estimates the translational and rotational components of the rigid transform through an iterative process and requires an initial approximation of the rotation and translation limits that depend on the dimension of the image and the initial overlap between images. The registration is performed in two ways: the same transform approach applies the transform computed for the end diastolic frame to all frames of the cardiac cycle, whereas the unique transform approach registers each frame independently. The proposed SMC and exhaustive search algorithms were evaluated for 3D transthoracic echocardiographic volumes recorded from 3 patients and 3 volunteers who participated in two different research studies conducted at the Mazankowski Alberta Heart Institute. The evaluations demonstrate that the same transform approach yielded a Dice score value of $0.716~\pm ~0.041$ for the left ventricle and required less computational time than the unique transform approach or exhaustive search. It was found that the SMC algorithm performs better than the exhaustive search at the 0.05 significance level using the paired t test. The accuracy was improved further using the Simple Elastix non-rigid registration algorithm to fix misalignments due to movement and breathing, with an overall Dice score value of $0.787~\pm ~0.038$ .

Abstract Identifying women at high risk of osteoporotic fracture from aromatase inhibitor (AI) therapy for breast cancer is largely based on known risk factors for healthy postmenopausal women, which might not accurately reflect the risk in breast cancer patients post-AI therapy. To determine whether a polygenic score associated with fracture in healthy women is also significant in women treated with AIs for breast cancer, we used data from a prospective observational cohort of 2152 women diagnosed with hormonal receptor positive breast cancer treated with AIs as the initial endocrine therapy and examined a polygenic score of heel quantitative ultrasound speed of sound (gSOS) in relation to incident osteoporotic fracture after AI therapy during a median 6.1 years of follow up after AI initiation. In multivariable models, patients with the second and third highest tertiles (T) versus the lowest tertile of gSOS had significantly lower risk of fracture (T2: adjusted HR = 0.61, 95% CI: 0.46-0.80; T3: adjusted HR = 0.53, 95% CI: 0.40-0.70). The lower risk of fracture in patients with the highest tertile of gSOS remained significant after further adjustment for BMD at the hip (T3: adjusted HR = 0.62, 95% CI: 0.42-0.91). In conclusion, our analysis showed gSOS as a novel genetic predictor for fracture risk independent of BMD among breast cancer patients treated with AIs. Future studies are warranted to evaluate the performance of incorporating gSOS in prediction models for the risk of AI-related fracture in breast cancer patients.

Vesicular stomatitis virus (VSV), comprising vesicular stomatitis New Jersey virus (VSNJV) and vesicular stomatitis Indiana virus (VSIV), emerges from its focus of endemic transmission in Southern Mexico to cause sporadic livestock epizootics in the Western United States. A dearth of information on the role of potential arthropod vectors in the endemic region hampers efforts to identify factors that enable endemicity and predict outbreaks. In a two-year, longitudinal study at five cattle ranches in Chiapas, Mexico, insect taxa implicated as VSV vectors (blackflies, sandflies, biting midges, and mosquitoes) were collected and screened for VSV RNA, livestock vesicular stomatitis (VS) cases were monitored, and serum samples were screened for neutralizing antibodies. VS cases were reported during the rainy (n = 20) and post-rainy (n = 2) seasons. Seroprevalence against VSNJV in adult cattle was very high (75–100% per ranch) compared with VSIV (0.6%, all ranches). All four potential vector taxa were sampled, and VSNJV RNA was detected in each of them (11% VSNJV-positive of 874 total pools), while VSIV RNA was only detected in four pools of mosquitoes. Our findings indicate that VSNJV is the dominant serotype across our sampling sites with a variety of potential insect vectors involved in its transmission throughout the year. Although no livestock cases were reported in Chiapas during the dry season, VSNJV was detected in insects during this period, suggesting that mechanisms other than transmission from livestock support VSV endemicity.

Summary: Many studies infer the role of neurons by asking what information can be decoded from their activity or by observing the consequences of perturbing their activity. An alternative approach is to consider information flow between neurons. We applied this approach to the parietal reach region (PRR) and the lateral intraparietal area (LIP) in posterior parietal cortex. Two complementary methods imply that across a range of reaching tasks, information flows primarily from PRR to LIP. This indicates that during a coordinated reach task, LIP has minimal influence on PRR and rules out the idea that LIP forms a general purpose spatial processing hub for action and cognition. Instead, we conclude that PRR and LIP operate in parallel to plan arm and eye movements, respectively, with asymmetric interactions that likely support eye-hand coordination. Similar methods can be applied to other areas to infer their functional relationships based on inferred information flow.

There is a need to develop user-friendly imaging tools estimating robust quantitative biomarkers (QIBs) from multiparametric (mp)MRI for clinical applications in oncology. Quantitative metrics derived from (mp)MRI can monitor and predict early responses to treatment, often prior to anatomical changes. We have developed a vendor-agnostic, flexible, and user-friendly MATLAB-based toolkit, MRI-Quantitative Analysis and Multiparametric Evaluation Routines (“MRI-QAMPER”, current release v3.0), for the estimation of quantitative metrics from dynamic contrast-enhanced (DCE) and multi-b value diffusion-weighted (DW) MR and MR relaxometry. MRI-QAMPER’s functionality includes generating numerical parametric maps from these methods reflecting tumor permeability, cellularity, and tissue morphology. MRI-QAMPER routines were validated using digital reference objects (DROs) for DCE and DW MRI, serving as initial approval stages in the National Cancer Institute Quantitative Imaging Network (NCI/QIN) software benchmark. MRI-QAMPER has participated in DCE and DW MRI Collaborative Challenge Projects (CCPs), which are key technical stages in the NCI/QIN benchmark. In a DCE CCP, QAMPER presented the best repeatability coefficient (RC = 0.56) across test–retest brain metastasis data, out of ten participating DCE software packages. In a DW CCP, QAMPER ranked among the top five (out of fourteen) tools with the highest area under the curve (AUC) for prostate cancer detection. This platform can seamlessly process mpMRI data from brain, head and neck, thyroid, prostate, pancreas, and bladder cancer. MRI-QAMPER prospectively analyzes dose de-escalation trial data for oropharyngeal cancer, which has earned it advanced NCI/QIN approval for expanded usage and applications in wider clinical trials.

Abstract Randomized clinical trials (RCT) represent the cornerstone of evidence-based medicine but are resource-intensive. We propose and evaluate a machine learning (ML) strategy of adaptive predictive enrichment through computational trial phenomaps to optimize RCT enrollment. In simulated group sequential analyses of two large cardiovascular outcomes RCTs of (1) a therapeutic drug (pioglitazone versus placebo; Insulin Resistance Intervention after Stroke (IRIS) trial), and (2) a disease management strategy (intensive versus standard systolic blood pressure reduction in the Systolic Blood Pressure Intervention Trial (SPRINT)), we constructed dynamic phenotypic representations to infer response profiles during interim analyses and examined their association with study outcomes. Across three interim timepoints, our strategy learned dynamic phenotypic signatures predictive of individualized cardiovascular benefit. By conditioning a prospective candidate’s probability of enrollment on their predicted benefit, we estimate that our approach would have enabled a reduction in the final trial size across ten simulations (IRIS: −14.8% ± 3.1%, p one-sample t-test = 0.001; SPRINT: −17.6% ± 3.6%, p one-sample t-test

Abstract The mass extinction at the Cretaceous–Palaeogene boundary is widely attributed to sudden and severe climate changes forced by bolide impact and/or flood basalt volcanism. In terrestrial depositional settings, these changes may potentially be recorded by palaeosols. To test the ability of pedogenic features to record both long‐term climate and shorter‐term changes preceding and following the Cretaceous–Palaeogene extinction event, palaeosols in the Upper Cretaceous (Maastrichtian) Naashoibito Member of the Ojo Alamo Formation and the lower Palaeocene (Danian) Nacimiento Formation in the San Juan Basin of north‐western New Mexico, USA, were examined, including data from previous studies. The fine‐grained facies of the Naashoibito Member comprises grey to greenish‐grey and red‐banded mudstones displaying pedogenic features including colour mottling, root traces, cutans, ped fabrics, pedogenic slickensides and calcareous nodules. Aside from a high‐chroma horizon at the formation base, palaeosols in the lower Nacimiento Formation are broadly similar to those observed in the Naashoibito Member. Lateral and vertical variability of the pedogenic features between correlated sections suggest that soil hydrology varied spatially and temporally from very saturated to seasonally well‐drained, with temporal variations controlled by basin sedimentation rates. Abrupt and/or catastrophic climate events precisely at the Cretaceous–Palaeogene boundary are not recorded due to an unconformity at the top of the Naashoibito Member. However, the presence of kaolinite in the clay mineral assemblage of the Nacimiento Formation, particularly near the formation base, but not in the Naashoibito Member, indicates episodic warmth and short (104 years) intervals of more intense weathering conditions during the very early Danian as compared to the late Maastrichtian. Aside from short warm intervals, the overall palaeoclimate during deposition of both formations was warm and consistently subhumid to humid and seasonal, suggesting no substantial long‐term (105–106) climate change took place across the Cretaceous–Palaeogene boundary in the San Juan Basin.

Abstract Background Policy is receiving increasing attention in the field of implementation science. However, there remains a lack of clear, concise guidance about how policy can be conceptualized in implementation science research. Building on Curran’s article “Implementation science made too simple”—which defines “the thing” as the intervention, practice, or innovation in need of implementation support—we offer a typology of four very basic ways to conceptualize policy in implementation science research. We provide examples of studies that have conceptualized policy in these different ways and connect aspects of the typology to established frameworks in the field. The typology simplifies and refines related typologies in the field. Four very basic ways to think about policy in implementation science research. 1) Policy as something to adopt: an evidence-supported policy proposal is conceptualized as “the thing” and the goal of research is to understand how policymaking processes can be modified to increase adoption, and thus reach, of the evidence-supported policy. Policy-focused dissemination research is well-suited to achieve this goal. 2) Policy as something to implement: a policy, evidence-supported or not, is conceptualized as “the thing” and the goal of research is to generate knowledge about how policy rollout (or policy de-implementation) can be optimized to maximize benefits for population health and health equity. Policy-focused implementation research is well-suited to achieve this goal. 3) Policy as context to understand: an evidence-supported intervention is “the thing” and policies are conceptualized as a fixed determinant of implementation outcomes. The goal of research is to understand the mechanisms through which policies affect implementation of the evidence-supported intervention. 4) Policy as strategy to use: an evidence-supported intervention is “the thing” and policy is conceptualized as a strategy to affect implementation outcomes. The goal of research is to understand, and ideally test, how policy strategies affect implementation outcomes related to the evidence-supported intervention. Conclusion Policy can be conceptualized in multiple, non-mutually exclusive ways in implementation science. Clear conceptualizations of these distinctions are important to advancing the field of policy-focused implementation science and promoting the integration of policy into the field more broadly.

BackgroundEnterotoxigenic E. coli (ETEC) is a leading cause of diarrheal morbidity and mortality in children, although the data on disease burden, epidemiology, and impact on health at the community level are limited.MethodsIn a longitudinal birth cohort study of 345 children followed until 24 months of age in Lima, Peru, we measured ETEC burden in diarrheal and non-diarrheal samples using quantitative PCR (LT, STh, and STp toxin genes), studied epidemiology and measured anthropometry in children.ResultsAbout 70% of children suffered from one or more ETEC diarrhea episodes. Overall, the ETEC incidence rate (IR) was 73 per 100 child-years. ETEC infections began early after birth causing 10% (8.9–11.1) ETEC-attributable diarrheal burden at the population level (PAF) in neonates and most of the infections (58%) were attributed to ST-ETEC [PAF 7.9% (1.9–13.5)] and LT + ST-ETEC (29%) of which all the episodes were associated with diarrhea. ETEC infections increased with age, peaking at 17% PAF (4.6–27.7%; p = 0.026) at 21 to 24 months. ST-ETEC was the most prevalent type (IR 32.1) with frequent serial infections in a child. The common colonization factors in ETEC diarrhea cases were CFA/I, CS12, CS21, CS3, and CS6, while in asymptomatic ETEC cases were CS12, CS6 and CS21. Only few (5.7%) children had repeated infections with the same combination of ETEC toxin(s) and CFs, suggested genotype-specific immunity from each infection. For an average ETEC diarrhea episode of 5 days, reductions of 0.060 weight-for-length z-score (0.007 to 0.114; p = 0.027) and 0.061 weight-for-age z-score (0.015 to 0.108; p = 0.009) were noted in the following 30 days.ConclusionThis study showed that ETEC is a significant pathogen in Peruvian children who experience serial infections with multiple age-specific pathotypes, resulting in transitory growth impairment.

PurposeTo assess the reproducibility of radiomic features (RFs) extracted from dynamic contrast-enhanced computed tomography (DCE-CT) scans of patients diagnosed with hepatocellular carcinoma (HCC) with regards to inter-observer variability and acquisition timing after contrast injection. The predictive ability of reproducible RFs for differentiating between the degrees of HCC differentiation is also investigated.MethodsWe analyzed a set of DCE-CT scans of 39 patients diagnosed with HCC. Two radiologists independently segmented the scans, and RFs were extracted from each sequence of the DCE-CT scans. The same lesion was segmented across the DCE-CT sequences of each patient's scan. From each lesion, 127 commonly used RFs were extracted. The reproducibility of RFs was assessed with regard to (i) inter-observer variability, by evaluating the reproducibility of RFs between the two radiologists; and (ii) timing of acquisition following contrast injection (inter- and intra-imaging phase). The reproducibility of RFs was assessed using the concordance correlation coefficient (CCC), with a cut-off value of 0.90. Reproducible RFs were used for building XGBoost classification models for the differentiation of HCC differentiation.ResultsInter-observer analyses across the different contrast-enhancement phases showed that the number of reproducible RFs was 29 (22.8%), 52 (40.9%), and 36 (28.3%) for the non-contrast enhanced, late arterial, and portal venous phases, respectively. Intra- and inter-sequence analyses revealed that the number of reproducible RFs ranged between 1 (0.8%) and 47 (37%), inversely related with time interval between the sequences. XGBoost algorithms built using reproducible RFs in each phase were found to be high predictive ability of the degree of HCC tumor differentiation.ConclusionsThe reproducibility of many RFs was significantly impacted by inter-observer variability, and a larger number of RFs were impacted by the difference in the time of acquisition after contrast injection. Our findings highlight the need for quality assessment to ensure that scans are analyzed in the same physiologic imaging phase in quantitative imaging studies, or that phase-wide reproducible RFs are selected. Overall, the study emphasizes the importance of reproducibility and quality control when using RFs as biomarkers for clinical applications.

The quality of ultrasound (US) imaging has been constrained by its limited contrast and resolution, inherent speckle noise, and the presence of other artifacts. Existing traditional and deep learning-based US denoising approaches have many limitations, such as reliance on manual parameter configurations, poor performance for unknown noise levels, the requirement for a large number of training data, and high computational expense. To address these challenges, we propose a novel Generative Adversarial Network (GAN) based denoiser. Capsule networks are utilized in both the generator and discriminator of the proposed GAN to capture intricate sparse features with less complexity. In addition, bias components are removed from all neurons of the generator to handle the unknown noise levels. A parallel attention module is also included in the proposed model to further enhance denoising performance. The proposed approach is trained in a semi-supervised manner and can thus be trained with fewer labeled images. Experimental evaluation on publicly available HC18 and BUSI datasets showed that the proposed approach achieved state-of-the-art denoising performance, with PSNR values of 33.86 and 34.16, and SSIM indices of 0.91 and 0.90, respectively. Moreover, experiments showed that the proposed approach is lightweight and more than twice as fast as similar denoisers.

BackgroundUnderstanding the relative contributions of SARS-CoV-2 infection-induced and vaccine-induced seroprevalence is key to measuring overall population-level seroprevalence and help guide policy decisions.MethodsUsing a series of six population-based cross-sectional surveys conducted among persons aged ≥7 years in a large health system with over 4.5 million members between May 2021 and April 2022, we combined data from the electronic health record (EHR), an electronic survey and SARS-CoV-2 spike antibody binding assay, to assess the relative contributions of infection and vaccination to population-level SARS-CoV-2 seroprevalence. EHR and survey data were incorporated to determine spike antibody positivity due to SARS-CoV-2 infection and COVID-19 vaccination. We used sampling and non-response weighting to create population-level estimates.ResultsWe enrolled 4,319 persons over six recruitment waves. SARS-CoV-2 spike antibody seroprevalence increased from 83.3% (CI 77.0-88.9) in May 2021 to 93.5% (CI 89.5-97.5) in April 2022. By April 2022, 68.5% (CI 61.9-74.3) of the population was seropositive from COVID-19 vaccination only, 13.9% (10.7-17.9) from COVID-19 vaccination and prior diagnosed SARS-CoV-2 infection, 8.2% (CI 4.5-14.5) from prior diagnosed SARS-CoV-2 infection only and 2.9% (CI 1.1-7.6) from prior undiagnosed SARS-CoV-2 infection only. We found high agreement (≥97%) between EHR and survey data for ascertaining COVID-19 vaccination and SARS-CoV-2 infection status.ConclusionsBy April 2022, 93.5% of persons had detectable SARS-CoV-2 spike antibody, predominantly from COVID-19 vaccination. In this highly vaccinated population and over 18 months into the pandemic, SARS-CoV-2 infection without COVID-19 vaccination was a small contributor to overall population-level seroprevalence.

IntroductionCessation of substance use, a facet of recovery, as well as mitigating stigma experienced by individuals with substance use disorder (SUD), are important to supporting health and well-being of those who use substances. But there is limited and mixed evidence on whether cessation of substance use has a positive impact on individuals’ stigma experiences. This study examined whether there were differences in stigma perceptions between those who self-report using substances and those who self-report not currently using substances associated with their SUD.Materials and methodsA survey was conducted among individuals in 10 counties of Michigan with self-identified history with SUD. The survey aimed to understand five dimensions of stigma perceptions: enacted stigma, anticipated stigma, internalized stigma, social withdrawal, and treatment stigma. Survey items for each measure were adapted from prior literature. The mean was calculated for each stigma measure for analyses. Data analyses tested whether there were significant differences in each of the five stigma domains between the two groups using either regression or t-test, depending on the necessity to include covariates.ResultsFindings suggested that among the five stigma domains, only internalized stigma showed statistically significant differences between the two groups (b = 0.19, se = 0.08, p

Contrast-enhanced computed tomography scans (CECT) are routinely used in the evaluation of different clinical scenarios, including the detection and characterization of hepatocellular carcinoma (HCC). Quantitative medical image analysis has been an exponentially growing scientific field. A number of studies reported on the effects of variations in the contrast enhancement phase on the reproducibility of quantitative imaging features extracted from CT scans. The identification and labeling of phase enhancement is a time-consuming task, with a current need for an accurate automated labeling algorithm to identify the enhancement phase of CT scans. In this study, we investigated the ability of machine learning algorithms to label the phases in a dataset of 59 HCC patients scanned with a dynamic contrast-enhanced CT protocol. The ground truth labels were provided by expert radiologists. Regions of interest were defined within the aorta, the portal vein, and the liver. Mean density values were extracted from those regions of interest and used for machine learning modeling. Models were evaluated using accuracy, the area under the curve (AUC), and Matthew's correlation coefficient (MCC). We tested the algorithms on an external dataset (76 patients). Our results indicate that several supervised learning algorithms (logistic regression, random forest, etc.) performed similarly, and our developed algorithms can accurately classify the phase of contrast enhancement.

Attenuation of adipose hormone sensitive lipase (HSL) may impair lipolysis and exacerbate obesity. We investigate the role of cytokine, macrophage migration inhibitory factor (MIF) in regulating adipose HSL and adipocyte hypertrophy. Extracellular MIF downregulates HSL in an autocrine fashion, by activating the AMPK/JNK signaling pathway upon binding to its membrane receptor, CD74. WT mice fed high fat diet (HFD), as well as mice overexpressing MIF, both had high circulating MIF levels and showed suppression of HSL during the development of obesity. Blocking the extracellular action of MIF by a neutralizing MIF antibody significantly reduced obesity in HFD mice. Interestingly, intracellular MIF binds with COP9 signalosome subunit 5 (Csn5) and JNK, which leads to an opposing effect to inhibit JNK phosphorylation. With global MIF deletion, adipocyte JNK phosphorylation increased, resulting in decreased HSL expression, suggesting that the loss of MIF's intracellular inhibitory action on JNK was dominant in Mif−/− mice. Adipose tissue from Mif−/− mice also exhibited higher Akt and lower PKA phosphorylation following HFD feeding compared with WT, which may contribute to the downregulation of HSL activation during more severe obesity. Both intracellular and extracellular MIF have opposing effects to regulate HSL, but extracellular actions predominate to downregulate HSL and exacerbate the development of obesity during HFD.

Abstract Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature. Using 2363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r2 in 5-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS’s association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.06–1.21, p = 4.0 × 10–4). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRSER-/ER+). Furthermore, its effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention.

Abstract Background The objective of this study was to evaluate the behavioral determinants associated with exclusive use of arsenic-safe water in the community-led Strong Heart Water Study (SHWS) arsenic mitigation program. Methods The SHWS is a randomized controlled trial of a community-led arsenic mitigation program designed to reduce arsenic exposure among private well users in American Indian Great Plains communities. All households received point-of-use (POU) arsenic filters installed at baseline and were followed for 2 years. Behavioral determinants selected were those targeted during the development of the SHWS program, and were assessed at baseline and follow-up. Results Among participants, exclusive use of arsenic-safe water for drinking and cooking at follow-up was associated with higher self-efficacy for accessing local resources to learn about arsenic (OR: 5.19, 95% CI: 1.48–18.21) and higher self-efficacy to resolve challenges related to arsenic in water using local resources (OR: 3.11, 95% CI: 1.11–8.71). Higher commitment to use the POU arsenic filter faucet at baseline was also a significant predictor of exclusive arsenic-safe water use for drinking (OR: 32.57, 95% CI: 1.42–746.70) and cooking (OR: 15.90, 95% CI: 1.33–189.52) at follow-up. From baseline to follow-up, the SHWS program significantly increased perceived vulnerability to arsenic exposure, self-efficacy, descriptive norms, and injunctive norms. Changing one’s arsenic filter cartridge after installation was associated with higher self-efficacy to obtain arsenic-safe water for drinking (OR: 6.22, 95% CI: 1.33–29.07) and cooking (OR: 10.65, 95% CI: 2.48–45.68) and higher perceived vulnerability of personal health effects (OR: 7.79, 95% CI: 1.17–51.98) from drinking arsenic-unsafe water. Conclusions The community-led SHWS program conducted a theory-driven approach for intervention development and evaluation that allowed for behavioral determinants to be identified that were associated with the use of arsenic safe water and changing one’s arsenic filter cartridge. These results demonstrate that theory-driven, context-specific formative research can influence behavior change interventions to reduce water arsenic exposure. The SHWS can serve as a model for the design of theory-driven intervention approaches that engage communities to reduce arsenic exposure. Trial registration The SHWS is registered with ClinicalTrials.gov (Identifier: NCT03725592).

Abstract Recovery from depression often demonstrates a nonlinear pattern of treatment response, where the largest reduction in symptoms is observed early followed by smaller improvements. This study investigated whether this exponential pattern could model the antidepressant response to repetitive transcranial magnetic stimulation (TMS). Symptom ratings from 97 patients treated with TMS for depression were collected at baseline and after every five sessions. A nonlinear mixed-effects model was constructed using an exponential decay function. This model was also applied to group-level data from several published clinical trials of TMS for treatment-resistant depression. These nonlinear models were compared to corresponding linear models. In our clinical sample, response to TMS was well modeled with the exponential decay function, yielding significant estimates for all parameters and demonstrating superior fit compared to a linear model. Similarly, when applied to multiple studies comparing TMS modalities as well as to previously identified treatment response trajectories, the exponential decay models yielded consistently better fits compared to linear models. These results demonstrate that the antidepressant response to TMS follows a nonlinear pattern of improvement that is well modeled with an exponential decay function. This modeling offers a simple and useful framework to inform clinical decisions and future studies.

Abstract Background Quantitative methods of Fluorodeoxyglucose Positron Emission Tomography (FDG‐PET) interpretation, including the percent change in FDG uptake from baseline (ΔSUV), are under investigation in lymphoma to overcome challenges associated with visual scoring systems (VSS) such as the Deauville 5‐point scale (5‐PS). Methods In CALGB 50303, patients with DLBCL received frontline R‐CHOP or DA‐EPOCH‐R, and although there were no significant associations between interim PET responses assessed centrally after cycle 2 (iPET) using 5‐PS with progression‐free survival (PFS) or overall survival (OS), there were significant associations between central determinations of iPET ∆SUV with PFS/OS. In this patient cohort, we retrospectively compared local vs central iPET readings and evaluated associations between local imaging data and survival outcomes. Results Agreement between local and central review was moderate (kappa = 0.53) for VSS and high (kappa = 0.81) for ∆SUV categories (

Abstract Purpose Deficits in speech understanding constitute one of the most severe consequences of hearing loss. Here we investigate the clinical and genetic risk factors for symmetric deterioration of speech recognition thresholds (SRT) among cancer survivors treated with cisplatin. Methods SRT was measured using spondaic words and calculating the mean of measurements for both ears with symmetric SRT values. For clinical associations, SRT‐based hearing disability (SHD) was defined as SRT≥15 dB hearing loss and clinical variables were derived from the study dataset. Genotyped blood samples were used for GWAS with rank‐based inverse normal transformed SRT values as the response variable. Age was used as a covariate in association analyses. Results SHD was inversely associated with self‐reported health (p = 0.004). Current smoking (p = 0.002), years of smoking (p = 0.02), BMI (p

Abstract Background Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. Methods To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. Results We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. Conclusions Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.

Stigma toward people taking medication for opioid use disorder (MOUD) is prevalent, harmful to the health and well-being of this population, and impedes MOUD treatment resource provision, help-seeking, and engagement in care. In recent years, clinicians have implemented new models of MOUD-based treatment in parts of the United States that integrate buprenorphine initiation into emergency departments and other acute general medical settings, with post-discharge linkage to office-based treatment. These service models increase access to MOUD and they have potential to mitigate stigma toward opioid use and MOUD. However, the empirical literature connecting these emerging service delivery models to stigma outcomes remains underdeveloped. This paper aims to bridge the stigma and health service literatures via a conceptual model delineating how elements of emerging MOUD service models can reduce stigma and increase behavior in pursuit of life goals. Specifically, we outline how new approaches to three key processes can counter structural, public, and self-stigma for this population: (1) community outreach with peer-to-peer influence, (2) clinical evaluation and induction of MOUD in acute care settings, and (3) transition to outpatient maintenance care and early recovery. Emerging service models that target these three processes can, in turn, foster patient empowerment and pursuit of life goals. There is great potential to increase the well-being of people who use opioids by reducing stigma against MOUD via these structural changes.

Background The recent World Health Organization (WHO) blueprint for dementia research and Lancet Commission on ending stigma and discrimination in mental health has identified a gap around dementia-related measures of stigma and discrimination that can be used in different cultural, language and regional contexts. Aims We aimed to characterise experiences of discrimination, and report initial psychometric properties of a new tool to capture these experiences, among a global sample of people living with dementia. Method We analysed data from 704 people living with dementia who took part in a global survey from 33 different countries and territories. Psychometric properties were examined, including internal consistency and construct validity. Results A total of 83% of participants reported discrimination in one or more areas of life, and this was similar across WHO Regions. The exploratory factor analysis factor loadings and scree plot supported a unidimensional structure for the Discrimination and Stigma Scale Ultra Short for People Living with Dementia (DISCUS-Dementia). The instrument demonstrated excellent internal consistency, with most of the construct validity hypotheses being confirmed and qualitative responses demonstrating face validity. Conclusions Our analyses suggest that the DISCUS-Dementia performs well with a global sample of people living with dementia. This scale can be integrated into large-scale studies to understand factors associated with stigma and discrimination. It can also provide an opportunity for a structured discussion around stigma and discrimination experiences important to people living with dementia, as well as planning psychosocial services and initiatives to reduce stigma and discrimination.

Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined high-dimensional spatial analyses with in vitro and in vivo modeling to study the mechanisms underlying immune infiltration in human multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). Clustered tumor growth was a feature of MM but not MGUS biopsies, and this growth pattern was reproduced in humanized mouse models. MM biopsies exhibited intralesional as well as spatial heterogeneity, with coexistence of T cell–rich and T cell–sparse regions and the presence of areas of T cell exclusion. In vitro studies demonstrated that T cell entry into MM clusters was regulated by agonistic signals and CD2-CD58 interactions. Upon adoptive transfer, antigen-specific T cells localized to the tumor site but required in situ DC–mediated antigen presentation for tumor entry. C-type lectin domain family 9 member A–positive (CLEC9A+) DCs appeared to mark portals of entry for gradients of T cell infiltration in MM biopsies, and their proximity to T cell factor 1–positive (TCF1+) T cells correlated with disease state and risk status. These data illustrate a role for tumor-associated DCs and in situ activation in promoting the infiltration of antigen-specific T cells in MM and provide insights into spatial alterations in tumor/immune cells with malignant evolution.

Introduction In high mortality settings, prophylactic azithromycin has been shown to improve birth weight and gestational age at birth when administered antenatally, to reduce the incidence of neonatal infections when administered intrapartum, and to improve survival when administered in infancy. Questions remain regarding whether azithromycin can prevent stillbirths, and regarding the optimal strategy for the delivery of azithromycin to pregnant women and their infants.Methods and analysis Sauver avec l’Azithromycine en Traitant les Femmes Enceintes et les Enfants (SANTE) is a 2×2 factorial, individually randomised, placebo-controlled, double-masked trial in rural Mali. The primary aims are: (1A) to assess the efficacy of antenatal and intrapartum azithromycin on a composite outcome of stillbirths and infant mortality through 6–12 months and (1B) to assess the efficacy of azithromycin administered concurrently with the first and third doses of pentavalent vaccines (Penta-1/3) on infant mortality through 6–12 months. Pregnant participants (n=49 600) and their infants are randomised 1:1:1:1 to one of four treatment arms: (1) mother and infant receive azithromycin, (2) mother and infant receive placebo, (3) mother receives azithromycin and infant receives placebo or (4) mother receives placebo and infant receives azithromycin. Pregnant participants receive three single 2 g doses: two antepartum and one intrapartum. Infants receive a single 20 mg/kg dose at the Penta-1 and 3 visits. An additional cohort of 12 000 infants is recruited at the Penta-1 visit and randomised 1:1 to receive azithromycin or placebo at the same time points. The SANTE trial will inform guidelines and policies regarding the administration of antenatal and infant azithromycin using routine healthcare delivery platforms.Ethics and dissemination This trial was approved by the Institutional Review Board at the University of Maryland School of Medicine (Protocol #HP-00084242) and the Faculté de Médecine et d’Odonto-Stomatologie in Mali. The findings of this trial will be published in open access peer-reviewed journals.Trial registration number NCT03909737.

O câncer de testículo é uma doença rara, sendo identificados 5000 casos novos por ano nos Estados Unidos. Apesar de representar somente 1% de todos os tumores masculinos, o câncer de testículo tem sido matéria de constante atenção por vários fatores.

Following the Pluto flyby of the New Horizons spacecraft, the mission provided a unique opportunity to explore the Kuiper Belt in situ. The possibility existed to fly by a Kuiper Belt object (KBO), as well as to observe additional objects at distances closer than are feasible from Earth-orbit facilities. However, at the time of launch no KBOs were known about that were accessible by the spacecraft. In this paper we present the results of 10 yr of observations and three uniquely dedicated efforts—two ground-based using the Subaru Suprime Camera, the Magellan MegaCam and IMACS Cameras, and one with the Hubble Space Telescope—to find such KBOs for study. In this paper we overview the search criteria and strategies employed in our work and detail the analysis efforts to locate and track faint objects in the Galactic plane. We also present a summary of all of the KBOs that were discovered as part of our efforts and how spacecraft targetability was assessed, including a detailed description of our astrometric analysis, which included development of an extensive secondary calibration network. Overall, these efforts resulted in the discovery of 85 KBOs, including 11 that became objects for distant observation by New Horizons and (486958) Arrokoth, which became the first post-Pluto flyby destination.

Abstract Background Substantial data from high-income countries support early interventions in the form of evidence-based Coordinated Specialty Care (CSC) for people experiencing First Episode Psychosis (FEP) to ameliorate symptoms and minimize disability. Chile is unique among Latin American countries in providing universal access to FEP services through a national FEP policy that mandates the identification of FEP individuals in primary care and guarantees delivery of community-based FEP treatments within a public health care system. Nonetheless, previous research has documented that FEP services currently provided at mental health clinics do not provide evidence-based approaches. This proposal aims to address this shortfall by first adapting OnTrackNY (OTNY), a CSC program currently being implemented across the USA, into OnTrackChile (OTCH), and then examine its effectiveness and implementation in Chile. Methods The Dynamic Adaptation Process will be used first to inform the adaptation and implementation of OTCH to the Chilean context. Then, a Hybrid Type 1 trial design will test its effectiveness and cost and evaluate its implementation using a cluster-randomized controlled trial (RCT) (N = 300 from 21 outpatient clinics). The OTCH program will be offered in half of these outpatient clinics to individuals ages 15-35. Usual care services will continue to be offered at the other clinics. Given the current COVID-19 pandemic, most research and intervention procedures will be conducted remotely. The study will engage participants over the course of 2 years, with assessments administered at enrollment, 12 months, and 24 months. Primary outcomes include implementation (fidelity, acceptability, and uptake) and service outcomes (person-centeredness, adherence, and retention). Secondary outcomes comprise participant-level outcomes such as symptoms, functioning, and recovery orientation. Over the course of the study, interviews and focus groups with stakeholders will be conducted to better understand the implementation of OTCH. Discussion Findings from this study will help determine the feasibility, effectiveness, and cost for delivering CSC services in Chile. Lessons learned about facilitators and barriers related to the implementation of the model could help inform the approach needed for these services to be further expanded throughout Latin America. Trial registration www.ClinicalTrials.gov NCT04247711 . Registered 30 January 2020. Trial status The OTCH trial is currently recruiting participants. Recruitment started on March 1, 2021, and is expected to be completed by December 1, 2022. This is the first version of this protocol (5/12/2021).

Abstract Background Bangladesh introduced the 10-valent pneumococcal conjugate vaccine (PCV10) for children aged

Abstract Background The use of archived formalin-fixed paraffin-embedded (FFPE) tumor tissues has become a common practice in clinical and epidemiologic genetic research. Simultaneous extraction of DNA and RNA from FFPE tissues is appealing but can be practically challenging. Here we report our results and lessons learned from processing FFPE breast tumor tissues for a large epidemiologic study. Methods Qiagen AllPrep DNA/RNA FFPE kit was adapted for dual extraction using tissue punches or sections from breast tumor tissues. The yield was quantified using Qubit and fragmentation analysis by Agilent Bioanalyzer. A subset of the DNA samples were used for genome-wide DNA methylation assays and RNA samples for sequencing. The QC metrices and performance of the assays were analyzed with pre-analytical variables. Results A total of 1859 FFPE breast tumor tissues were processed. We found it critical to adjust proteinase K digestion time based on tissue volume to achieve balanced yields of DNA and RNA. Tissue punches taken from tumor-enriched regions provided the most reliable output. A median of 1475 ng DNA and 1786 ng RNA per sample was generated. The median DNA integrity number (DIN) was 3.8 and median DV200 for RNA was 33.2. Of 1294 DNA samples used in DNA methylation assays, 97% passed quality check by qPCR and 92% generated data deemed high quality. Of the 130 RNA samples with DV200 ≥ 20% used in RNA-sequencing, all but 5 generated usable transcriptomic data with a mapping rate ≥ 60%. Conclusions Dual DNA/RNA purification using Qiagen AllPrep FFPE extraction protocol is feasible for clinical and epidemiologic studies. We recommend tissue punches as a reliable source material and fine tuning of proteinase K digestion time based on tissue volume. Impact Our protocol and recommendations may be adapted by future studies for successful extraction of archived tumor tissues.

Abstract Purpose Cisplatin is a critical component of first‐line chemotherapy for several cancers, but causes peripheral sensory neuropathy, hearing loss, and tinnitus. We aimed to identify comorbidities for cisplatin‐induced neurotoxicities among large numbers of similarly treated patients without the confounding effect of cranial radiotherapy. Methods Utilizing linear and logistic regression analyses on 1680 well‐characterized cisplatin‐treated testicular cancer survivors, we analyzed associations of hearing loss, tinnitus, and peripheral neuropathy with nongenetic comorbidities. Genome‐wide association studies and gene‐based analyses were performed on each phenotype. Results Hearing loss, tinnitus, and peripheral neuropathy, accounting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension and poorer self‐reported health. In addition, hearing loss was positively associated with BMIs at clinical evaluation and nonwork‐related noise exposure (>5 h/week). Tinnitus was positively associated with tobacco use, hypercholesterolemia, and noise exposure. We observed positive associations between peripheral neuropathy and persistent vertigo, tobacco use, and excess alcohol consumption. Hearing loss and TXNRD1, which plays a key role in redox regulation, showed borderline significance (p = 4.2 × 10−6) in gene‐based analysis. rs62283056 in WFS1 previously found to be significantly associated with hearing loss (n = 511), was marginally significant in an independent replication cohort (p = 0.06; n = 606). Gene‐based analyses identified significant associations between tinnitus and WNT8A (p = 2.5 × 10−6), encoding a signaling protein important in germ cell tumors. Conclusions Genetics variants in TXNRD1 and WNT8A are notable risk factors for hearing loss and tinnitus, respectively. Future studies should investigate these genes and if replicated, identify their potential impact on preventive strategies.

Summary: While insulin resistance (IR) is associated with inflammation in white adipose tissue, we report a non-inflammatory adipose mechanism of high fat-induced IR mediated by loss of Pref-1. Pref-1, released from adipose Pref-1+ cells with characteristics of M2 macrophages, endothelial cells or progenitors, inhibits MIF release from both Pref-1+ cells and adipocytes by binding with integrin β1 and inhibiting the mobilization of p115. High palmitic acid induces PAR2 expression in Pref-1+ cells, downregulating Pref-1 expression and release in an AMPK-dependent manner. The loss of Pref-1 increases adipose MIF secretion contributing to non-inflammatory IR in obesity. Treatment with Pref-1 blunts the increase in circulating plasma MIF levels and subsequent IR induced by a high palmitic acid diet. Thus, high levels of fatty acids suppress Pref-1 expression and secretion, through increased activation of PAR2, resulting in an increase in MIF secretion and a non-inflammatory adipose mechanism of IR.

BackgroundThe World Health Organization (WHO) recommends systematic symptom screening for tuberculosis (TB). However, TB prevalence surveys suggest that this strategy does not identify millions of TB patients, globally. Undiagnosed or delayed diagnosis of TB contribute to TB transmission and exacerbate morbidity and mortality. We conducted a cluster-randomized trial of large urban and rural primary healthcare clinics in 3 provinces of South Africa to evaluate whether a novel intervention of targeted universal testing for TB (TUTT) in high-risk groups diagnosed more patients with TB per month compared to current standard of care (SoC) symptom-directed TB testing.Methods and findingsSixty-two clinics were randomized; with initiation of the intervention clinics over 6 months from March 2019. The study was prematurely stopped in March 2020 due to clinics restricting access to patients, and then a week later due to the Coronavirus Disease 2019 (COVID-19) national lockdown; by then, we had accrued a similar number of TB diagnoses to that of the power estimates and permanently stopped the trial. In intervention clinics, attendees living with HIV, those self-reporting a recent close contact with TB, or a prior episode of TB were all offered a sputum test for TB, irrespective of whether they reported symptoms of TB. We analyzed data abstracted from the national public sector laboratory database using Poisson regression models and compared the mean number of TB patients diagnosed per clinic per month between the study arms. Intervention clinics diagnosed 6,777 patients with TB, 20.7 patients with TB per clinic month (95% CI 16.7, 24.8) versus 6,750, 18.8 patients with TB per clinic month (95% CI 15.3, 22.2) in control clinics during study months. A direct comparison, adjusting for province and clinic TB case volume strata, did not show a significant difference in the number of TB cases between the 2 arms, incidence rate ratio (IRR) 1.14 (95% CI 0.94, 1.38, p = 0.46). However, prespecified difference-in-differences analyses showed that while the rate of TB diagnoses in control clinics decreased over time, intervention clinics had a 17% relative increase in TB patients diagnosed per month compared to the prior year, interaction IRR 1.17 (95% CI 1.14, 1.19, p < 0.001). Trial limitations were the premature stop due to COVID-19 lockdowns and the absence of between-arm comparisons of initiation and outcomes of TB treatment in those diagnosed with TB.ConclusionsOur trial suggests that the implementation of TUTT in these 3 groups at extreme risk of TB identified more TB patients than SoC and could assist in reducing undiagnosed TB patients in settings of high TB prevalence.Trial registrationSouth African National Clinical Trials Registry DOH-27-092021-4901.

IntroductionAnger can engender action by individuals and groups. It is thus important to understand anger’s behavioral phenotypes and their underlying neural substrates. Here, we introduce a construct we term agentic anger, a negatively valenced internal state that motivates action to achieve risky goals. We evaluate our neurobehavioral model via testable hypotheses in two proof-of-concept studies.Study 1 MethodsStudy 1 used the Incentive Balloon Analogue Risk Task in a within-subjects, repeated measures design in 39 healthy volunteers to evaluate: (a) impact of blockade of reward on agentic anger, assessed by self-reports of negative activation (NA), (b) impact of achievement of reward on exuberance, assessed by self-reports of positive activation (PA), (c) the interrelationship of these valenced states, and (d) their relationship with personality.Study 1 ResultsTask-induced NA was positively correlated with task-induced PA, risk-taking on the task and trait Social Potency (SP), a measure of trait agency and reward sensitivity on the Multidimensional Personality Questionnaire Brief-Form.Study 2 MethodsStudy 2 assessed functional MRI response to stakes for risk-taking in healthy volunteers receiving 20 mg d-amphetamine in a double-blinded, placebo-controlled crossover design (N = 10 males), providing preliminary information on ventral striatal response to risky rewards during catecholamine activation.Study 2 ResultsTrait SP and task-induced PA were strongly positively related to catecholamine-facilitated BOLD response in the right nucleus accumbens, a brain region where DA prediction error signal shapes action value and selection. Participants’ task-induced NA was strongly positively related with trait SP and task-induced PA, replicating the findings of Study 1.DiscussionTogether these results inform the phenomenology and neurobiology of agentic anger, which recruits incentive motivational circuitry and motivates personal action in response to goals that entail risk (defined as exposure to uncertainty, obstacles, potential harm, loss and/or financial, emotional, bodily, or moral peril). Neural mechanisms of agency, anger, exuberance, and risk-taking are discussed, with implications for personal and group action, decision-making, social justice, and behavior change.

IntroductionThe COVID-19 pandemic has had a variable effect on vulnerable populations, including patients with chronic pain who rely on opioid treatment or have comorbid opioid use disorder. Limited access to care due to isolation measures may lead to increased pain severity, worse mental health symptoms, and adverse opioid-related outcomes. This scoping review aimed to understand the impact of the COVID-19 pandemic on the dual epidemics of chronic pain and opioids in marginalized communities worldwide.MethodsSearches of primary databases including PubMed, Web of Science, Scopus, and PsycINFO were performed in March 2022, restricting the publication date to December 1, 2019. The search yielded 685 articles. After title and abstract screening, 526 records were screened by title and abstract, 87 through full-text review, of which 25 articles were included in the final analysis.ResultsOur findings illuminate the differential distribution of pain burden across marginalized groups and how it serves to heighten existing disparities. Service disruptions due to social distancing orders and infrastructural limitations prevented patients from receiving the care they needed, resulting in adverse psychological and physical health outcomes. Efforts to adapt to COVID-19 circumstances included modifications to opioid prescribing regulations and workflows and expanded telemedicine services.ConclusionResults have implications for the prevention and management of chronic pain and opioid use disorder, such as challenges in adopting telemedicine in low-resource settings and opportunities to strengthen public health and social care systems with a multidisciplinary and multidimensional approach.

Abstract We conducted a pilot trial of an intervention targeting intersectional stigma related to being pregnant and living with HIV while promoting capabilities for achieving ‘respected motherhood’ (‘what matters most’) in Botswana. A pragmatic design allocated participants to the intervention (N = 44) group and the treatment-as-usual (N = 15) group. An intent-to-treat, difference-in-difference analysis found the intervention group had significant decreases in HIV stigma (d = − 1.20; 95% CI − 1.99, − 0.39) and depressive symptoms (d = − 1.96; 95% CI − 2.89, − 1.02) from baseline to 4-months postpartum. Some, albeit less pronounced, changes in intersectional stigma were observed, suggesting the importance of structural-level intervention components to reduce intersectional stigma.

Abstract Background Transfusion-transmitted infections (TTIs) are a global health challenge. One new approach to reduce TTIs is the use of pathogen reduction technology (PRT). In vitro, Mirasol PRT reduces the infectious load in whole blood (WB) by at least 99%. However, there are limited in vivo data on the safety and efficacy of Mirasol PRT. The objective of the Mirasol Evaluation of Reduction in Infections Trial (MERIT) is to investigate whether Mirasol PRT of WB can prevent seven targeted TTIs (malaria, bacteria, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, and human herpesvirus 8). Methods MERIT is a randomized, double-blinded, controlled clinical trial. Recruitment started in November 2019 and is expected to end in 2024. Consenting participants who require transfusion as medically indicated at three hospitals in Kampala, Uganda, will be randomized to receive either Mirasol-treated WB (n = 1000) or standard WB (n = 1000). TTI testing will be performed on donor units and recipients (pre-transfusion and day 2, day 7, week 4, and week 10 after transfusion). The primary endpoint is the cumulative incidence of one or more targeted TTIs from the Mirasol-treated WB vs. standard WB in a previously negative recipient for the specific TTI that is also detected in the donor unit. Log-binomial regression models will be used to estimate the relative risk reduction of a TTI by 10 weeks associated with Mirasol PRT. The clinical effectiveness of Mirasol WB compared to standard WB products in recipients will also be evaluated. Discussion Screening infrastructure for TTIs in low-resource settings has gaps, even for major TTIs. PRT presents a fast, potentially cost-effective, and easy-to-use technology to improve blood safety. MERIT is the largest clinical trial designed to evaluate the use of Mirasol PRT for WB. In addition, this trial will provide data on TTIs in Uganda. Trial registration Mirasol Evaluation of Reduction in Infections Trial (MERIT) NCT03737669 . Registered on 9 November 2018

As humanity prepares for extended lunar exploration, understanding the radiation environment on the Moon is important for astronaut safety. This study utilized the Particle and Heavy-Ion Transport code System (PHITS), a stochastic Monte Carlo-based radiation transport code, to simulate the radiation environment inside a habitat, focusing on the impact of galactic cosmic rays (GCRs) interacting with local lunar and habitat material, and to calculate the effective dose equivalent. Placing a lunar base in a crater can provide additional shielding by reducing the GCR flux incident on the base. Furthermore, the secondary radiation field created by GCR interactions may be altered by the local topological features. GCR transport calculations were performed for a hypothetical base on a flat surface and in shallow and deep craters to determine the overall efficacy in dose reduction gained by placing a base in a 100 m diameter crater. Our findings indicate that the depth of lunar habitats significantly influences the effective dose equivalent, with deeper locations offering substantial protection. Specifically, alongside a crater wall at a deep depth (15 m), in solar minimum conditions, the total dose was reduced by approximately 44.9% compared to the dose at the surface. Similarly, at a shallow depth (5 m), a reduction of approximately 10.7% was observed. As the depth of the crater increased, the neutron contribution to the total dose also increased. Comparing the simulated doses to NASA’s lifetime exposure limits provides insights into mission planning and astronaut safety, emphasizing the importance of strategic habitat placement and design.

Standard-of-care medical imaging techniques such as CT, MRI, and PET play a critical role in managing patients diagnosed with metastatic cutaneous melanoma. Advancements in artificial intelligence (AI) techniques, such as radiomics, machine learning, and deep learning, could revolutionize the use of medical imaging by enhancing individualized image-guided precision medicine approaches. In the present article, we will decipher how AI/radiomics could mine information from medical images, such as tumor volume, heterogeneity, and shape, to provide insights into cancer biology that can be leveraged by clinicians to improve patient care both in the clinic and in clinical trials. More specifically, we will detail the potential role of AI in enhancing detection/diagnosis, staging, treatment planning, treatment delivery, response assessment, treatment toxicity assessment, and monitoring of patients diagnosed with metastatic cutaneous melanoma. Finally, we will explore how these proof-of-concept results can be translated from bench to bedside by describing how the implementation of AI techniques can be standardized for routine adoption in clinical settings worldwide to predict outcomes with great accuracy, reproducibility, and generalizability in patients diagnosed with metastatic cutaneous melanoma.