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Background: Intraoperative physiologic parameters could offer predictive utility in evaluating risk of adverse postoperative events yet are not included in current standard risk models. This study examined whether the inclusion of continuous intraoperative data improved machine learning model predictions for multiple outcomes after coronary artery bypass grafting, including 30-day mortality, renal failure, reoperation, prolonged ventilation, and combined morbidity and mortality (MM). Methods: The Society of Thoracic Surgeons (STS) database features and risk scores were combined with retrospectively gathered continuous intraoperative data from patients. Risk models were developed for each outcome by training a logistic regression classifier on intraoperative data using 5-fold cross-validation. STS risk scores were included as offset terms in the models. Results: Compared with the STS Risk Calculator, models developed using a combination of the intraoperative features and the STS preoperative risk score had improved mean area under the receiver operating characteristic curve for prolonged ventilation (0.750 [95% CI, 0.690-0.809] vs 0.800 [95% CI, 0.750-0.851]) and MM (0.695 [95% CI, 0.644-0.746] vs 0.724 [95% CI, 0.673-0.775]). Additionally, models developed using intraoperative features had improved calibration, measured with Brier score, for prolonged ventilation (0.060 [95% CI, 0.050-0.070] vs 0.055 [95% CI, 0.045-0.065]) and MM (0.092 [95% CI, 0.081-0.103] vs 0.087 [95% CI, 0.075-0.098]). Conclusions: The inclusion of time series intraoperative data in risk models may improve early postoperative care by identifying patients who require closer monitoring postoperatively.

The automated soft matter indenter (ASMI) is a platform for rapidly performing mechanical characterization of samples with elastic moduli in the range 7 kPa to 67 MPa with a sample acquisition time between 1 and 10 min. It is a low-cost system based upon open-source software, a modified mill, and an educational force sensor with a total bill of materials

Extramammary Paget disease (EMPD) is a rare dermatologic malignancy with a high rate of recurrence and increased risk for developing secondary malignancies. We present a 74-year-old male with previously resected primary EMPD who presented with widespread PSMA-avid lesions without prostatic uptake, an elevated PSA >100, and a negative prostate biopsy. Based on this and immunohistological staining, recurrent EMPD was suspected. However, after additional staining and reexamining their clinical presentation, metastatic prostate cancer without a detected primary lesion is more probable. This case highlights the diagnostic challenge variable expression of shared biomarkers found in EMPD and prostate cancer present to clinicians.

We examined the feeding ecology of planktonic crustaceans at three waterbodies situated across a latitudinal gradient in Europe (Croatia, Poland, Lithuania) using stable isotope measurements (δ13C, δ15N) in animal tissues. Relative, lake-specific values of δ15N showed that in all lakes, calanoid copepods occupied the highest trophic position, while Daphnia sp. and Diaphanosoma sp. were located closer to primary producers with Cyclopoid copepods located between these groups. We found a negative correlation between C:N ratio (proxy for lipid content) and δ15N, which indicates lipid content declined with the trophic level of the animals. Employment of stable isotope-based approach allows better recognition of trophic linkages than could be inferred from classical methods, and therefore our results contribute improvement of management strategies developed for aquatic ecosystems.

Summary: Background: Given the rapidly growing burden of cardiovascular disease (CVD) in Asia, this study forecasts the CVD burden and associated risk factors in Asia from 2025 to 2050. Methods: Data from the Global Burden of Disease 2019 study was used to construct regression models predicting prevalence, mortality, and disability-adjusted life years (DALYs) attributed to CVD and risk factors in Asia in the coming decades. Findings: Between 2025 and 2050, crude cardiovascular mortality is expected to rise 91.2% despite a 23.0% decrease in the age-standardised cardiovascular mortality rate (ASMR). Ischaemic heart disease (115 deaths per 100,000 population) and stroke (63 deaths per 100,000 population) will remain leading drivers of ASMR in 2050. Central Asia will have the highest ASMR (676 deaths per 100,000 population), more than three-fold that of Asia overall (186 deaths per 100,000 population), while high-income Asia sub-regions will incur an ASMR of 22 deaths per 100,000 in 2050. High systolic blood pressure will contribute the highest ASMR throughout Asia (105 deaths per 100,000 population), except in Central Asia where high fasting plasma glucose will dominate (546 deaths per 100,000 population). Interpretation: This forecast forewarns an almost doubling in crude cardiovascular mortality by 2050 in Asia, with marked heterogeneity across sub-regions. Atherosclerotic diseases will continue to dominate, while high systolic blood pressure will be the leading risk factor. Funding: This was supported by the NUHS Seed Fund (NUHSRO/2022/058/RO5+6/Seed-Mar/03), National Medical Research Council Research Training Fellowship (MH 095:003/008-303), National University of Singapore Yong Loo Lin School of Medicine's Junior Academic Fellowship Scheme, NUHS Clinician Scientist Program (NCSP2.0/2024/NUHS/NCWS) and the CArdiovascular DiseasE National Collaborative Enterprise (CADENCE) National Clinical Translational Program (MOH-001277-01).

Objectives: The aim of this study was to describe the epidemiology of injuries; time-loss and non-time loss, in elite male academy cricket. Design: Prospective cohort analysis. Methods: Annual injury incidence and prevalence from all cricket related injuries were calculated for 348 male academy players (under-13 to under-18) from the 18 First-Class County Cricket clubs in England and Wales across four years (2017/18, 2018/19, 2020/21 and 2021/22), in accordance with the updated consensus statement for injury surveillance methods in cricket. Results: The average annual injury incidence was 115.0 injuries/100 players/year, with similar rates between time-loss (59.7 injuries/100 players/year) and non-time loss injury incidence (55.3 injuries/100 players/year). On average, 8.5 ​% of players were unavailable on any given day of the year due to injury. Match injury incidence (48.8 injuries/100 players/year) was higher than cricket-based training (25.2 injuries/100 players/year), gym-based training, illness, and ‘other’ injury incidences. Match bowling was the activity associated with the highest total (17.7 injuries/100 players/year), time-loss (10.3 injuries/100 players/year) and non-time loss (7.4 injuries/100 players/year) injury incidence. The lumbar spine was the body location most frequently injured (15.3 injuries/100 players/year) and was the most prevalent body location injured (2.9 ​% of players). Conclusions: The findings from this study provide, robust evidence of the extent of the injury problem in elite male academy cricketers. Bowling poses the greatest risk to players and the lumbar spine is the most common and prevalent injury location.

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism.Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [18F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR.On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB.These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

Purpose: The pattern of flortaucipir tau PET uptake is topographically similar to the pattern of magnetic susceptibility in progressive supranuclear palsy (PSP); both with increased signal in subcortical structures such as the basal ganglia and midbrain, suggesting that they may be closely related. However, their relationship remains unknown since no studies have directly compared these two modalities in the same PSP cohort. We hypothesized that some flortaucipir uptake in PSP is associated with magnetic susceptibility, and hence iron deposition. The aim of this study was to evaluate the regional relationship between flortaucipir uptake and magnetic susceptibility and to examine the effects of susceptibility on flortaucipir uptake in PSP. Methods: Fifty PSP patients and 67 cognitively normal controls were prospectively recruited and underwent three Tesla MRI and flortaucipir tau PET scans. Quantitative susceptibility maps were reconstructed from multi-echo gradient-echo MRI images. Region of interest (ROI) analysis was performed to obtain flortaucipir and susceptibility values in the subcortical regions. Relationships between flortaucipir and susceptibility signals were evaluated using partial correlation analysis in the subcortical ROIs and voxel-based analysis in the whole brain. The effects of susceptibility on flortaucipir uptake were examined by using the framework of mediation analysis. Results: Both flortaucipir and susceptibility were greater in PSP compared to controls in the putamen, pallidum, subthalamic nucleus, red nucleus, and cerebellar dentate (p

Primary progressive aphasia (PPA) variants present with distinct disruptions in speech-language functions with little known about the interplay between affected and spared regions within the speech-language network and their interaction with other functional networks.The Neurodegenerative Research Group, Mayo Clinic, recruited 123 patients with PPA (55 logopenic (lvPPA), 44 non-fluent (nfvPPA) and 24 semantic (svPPA)) who were matched to 60 healthy controls. We investigated functional connectivity disruptions between regions within the left-speech-language network (Broca, Wernicke, anterior middle temporal gyrus (aMTG), supplementary motor area (SMA), planum temporale (PT) and parietal operculum (PO)), and disruptions to other networks (visual association, dorsal-attention, frontoparietal and default mode networks (DMN)).Within the speech-language network, multivariate linear regression models showed reduced aMTG-Broca connectivity in all variants, with lvPPA and nfvPPA findings remaining significant after Bonferroni correction. Additional loss in Wernicke-Broca connectivity in nfvPPA, Wernicke-PT connectivity in lvPPA and greater aMTG-PT connectivity in svPPA were also noted. Between-network connectivity findings in all variants showed reduced aMTG-DMN and increased aMTG-dorsal-attention connectivity, with additional disruptions between aMTG-visual association in both lvPPA and svPPA, aMTG-frontoparietal in lvPPA, and Wernicke-DMN breakdown in svPPA.These findings suggest that aMTG connectivity breakdown is a shared feature in all PPA variants, with lvPPA showing more extensive connectivity disruptions with other networks.

Aminophospholipids (aPL) such as phosphatidylserine are essential for supporting the activity of coagulation factors, circulating platelets, and blood cells. Phosphatidylthreonine (PT) is an aminophospholipid previously reported in eukaryotic parasites and animal cell cultures, but not yet in human tissues. Here, we evaluated whether PT is present in blood cells and characterized its ability to support coagulation. Several PT molecular species were detected in human blood, washed platelets, extracellular vesicles, and isolated leukocytes from healthy volunteers using liquid chromatography–tandem mass spectrometry. The ability of PT to support coagulation was demonstrated in vitro using biochemical and biophysical assays. In liposomes, PT supported prothrombinase activity in the presence and absence of phosphatidylserine. PT nanodiscs strongly bound FVa and lactadherin (nM affinity) but poorly bound prothrombin and FX, suggesting that PT supports prothrombinase through recruitment of FVa. PT liposomes bearing tissue factor poorly generated thrombin in platelet poor plasma, indicating that PT poorly supports extrinsic tenase activity. On platelet activation, PT is externalized and partially metabolized. Last, PT was significantly higher in platelets and extracellular vesicle from patients with coronary artery disease than in healthy controls. In summary, PT is present in human blood, binds FVa and lactadherin, supports coagulation in vitro through FVa binding, and is elevated in atherosclerotic vascular disease. Our studies reveal a new phospholipid subclass, that contributes to the procoagulant membrane, and may support thrombosis in patients at elevated risk.

Summary: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase with important roles in many cellular processes as well as in cancer and other diseases. EGF binding promotes EGFR dimerization and autophosphorylation through interactions that are well understood structurally. How these dimers relate to higher-order EGFR oligomers seen in cell membranes, however, remains unclear. Here, we used single-particle tracking (SPT) and Förster resonance energy transfer imaging to examine how each domain of EGFR contributes to receptor oligomerization and the rate of receptor diffusion in the cell membrane. Although the extracellular region of EGFR is sufficient to drive receptor dimerization, we find that the EGF-induced EGFR slowdown seen by SPT requires higher-order oligomerization—mediated in part by the intracellular tyrosine kinase domain when it adopts an active conformation. Our data thus provide important insight into the interactions required for higher-order EGFR assemblies involved in EGF signaling.

The executive function (EF) domains of working memory (WM), response inhibition (RI), and set shifting (SS) show maturational gains and are linked to neuroimaging-measured brain changes. This study explored ways in which maturation-linked differences in EF abilities are systematically associated with white matter microstructural differences from adolescence into young adulthood. Diffusion tensor imaging (DTI) and nine neurocognitive tests were collected from 120 healthy subjects ages 12–24. Analyses across the white matter skeleton were performed, focusing on fractional anisotropy (FA). Data were ‘fused’ using a multivariate technique (CCA+jICA), producing four independent components (ICs) depicting white matter FA values that covaried with test performance. Correlations between age and IC loading coefficients identified three EF-DTI profiles that may change developmentally. In one, SS performance was linked to greater reliance on the FA of ventral brain tracts, and less on dorsal tracts with age. In another, white matter microstructure was related to a pattern of strong WM and weak SS that became more pronounced with age. A final IC revealed that younger individuals with low RI and high WM/SS skills typically matured out of this cognitive imbalance, underscored by white matter changes with age. These novel multivariate results begin to emphasize the complexity of brain structure-cognition relationships in adolescents and young adults.

Drug delivery approaches can be used to enhance the bioavailability of current antiretroviral drugs used to treat HIV. Lipid nanocarriers are attractive drug delivery vehicles and these systems can be classified based on their lipid composition into solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs) and nanoemulsions (NEs). In order to develop high drug loading nanoformulations for the treatment of HIV, we investigate the factors that influence the comparative production of SLNs, NLCs and NEs with Imwitor 900k and soybean oil as the solid and liquid lipids respectively. These nanoformulations contained a therapeutically relevant drug mixture of darunavir (DRV) and ritonavir (RTV). We used a simple nanoprecipitation method that does not require any heating of the lipid phase and screened three key formulation factors (lipid concentration, surfactant selection and drug loading) in order to determine their effect on the particle properties and stability of the formulations. Two different surfactants were used, (Brij 78 and Tween 80) which had a significant effect on the ability to form a viable nanodispersion; using Brij 78 as the surfactant resulted in more viable formulations for our lipids. A concentration of the lipid in the organic phase of 4 mg/mL was determined to achieve a good balance between viable formulations and lipid loading resulting in nanoparticles with mean diameters ∼200–300 ​nm. Drug loadings of 10% w/w DRV/total lipid was achieved for SLNs, with loadings of 20% w/w was possible for NLCs and NEs, these values are amongst the highest reported for lipid nanoformulations. All formulations had encapsulation efficiencies of ≥92.5%. Overall, this study shows the versatility of the nanoprecipitation method for producing SLNs, NLCs and NEs. The ability to produce all three formulations with identical compositions (other than the lipids) may allow direct comparison of the biological properties in the future.

Background and Aims: Hypoxia in the intestinal epithelium can be caused by acute ischemic events or chronic inflammation in which immune cell infiltration produces inflammatory hypoxia starving the mucosa of oxygen. The epithelium has the capacity to regenerate after some ischemic and inflammatory conditions suggesting that intestinal stem cells (ISCs) are highly tolerant to acute and chronic hypoxia; however, the impact of hypoxia on human ISC (hISC) function has not been reported. Here we present a new microphysiological system (MPS) to investigate how hypoxia affects hISCs from healthy donors and test the hypothesis that prolonged hypoxia modulates how hISCs respond to inflammation-associated interleukins (ILs). Methods: hISCs were exposed to

Identifying strategies that offer co-benefits for biodiversity protection, forest restoration and human well-being are important for successful conservation outcomes. In this study, we identified opportunities where forest restoration and rehabilitation programs in Colombia also align with priority areas for the conservation of Neotropical migratory birds. We used citizen science eBird-based abundance estimates to define regions with the highest richness of Neotropical migratory birds of conservation concern at montane elevations in Colombia and aligned these high richness areas with domestic initiatives for forest protection (Forest Areas), restoration (Restoration Areas) and rehabilitation (Rehabilitation Areas). We quantified the location and amounts of these three areas as well as the type of land protection and designation within them, specifically, National Protected Areas, Indigenous Reserves, Afro-descendent territories, and regions affected by poverty and violence that are prioritized for rural development by the Colombian government in Post-conflict Territorially Focused Development Programs (PDET). Almost half of Forest Areas overlapped with PDETs where goals for economic development present a risk of forest loss if not done sustainably. There was a 20% overlap between Forest Areas and Afro-descendant territories and indigenous reserves; most of this overlap was outside of established protected areas thus presenting an opportunity for community forest conservation that benefits migratory birds. We found an alignment of less than 6% between migrant bird focal areas and the priority Restoration and Rehabilitation Areas identified by the Colombian National Restoration Plan indicating less opportunity for these programs to simultaneously benefit Neotropical migrant species. Our approach highlights that timely and efficient conservation of declining migrants depends on identifying the regions and strategies that incorporate local communities as part of the solution to forest loss and degradation in Colombia.

Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) is a rare type of T-Cell (non-Hodgkin's) lymphoma associated with the use of silicone breast implants. Recent widespread awareness has focused not only on the management of this condition but also in regards to potential litigation of surgeons, clinics, and breast implant manufacturers. Allegations of causation and inappropriate patient consent are being raised. The purpose of this article is to establish the timeline of relevant discoveries regarding this condition and associated implications with regards to appropriate informed patient consent.

Background: The purpose of this study is to assess which minimally invasive colon surgery approach may be associated with the least 30- and 90-day inpatient readmission costs from a payer perspective. Methods: This retrospective claims analysis included adult Medicare and commercially insured beneficiaries who underwent minimally invasive sigmoid, left, or right colon surgery between January 2016 and December 2019. Two cohorts were created based on the use of near-infrared fluorescence (NIF) and were propensity-score matched 1 NIF:5 NoNIF. Four subgroups were then created based on the presence of robotics (R): NIF-NoR, NIF-R, NoNIF-R, and NoNIF-NoR. Results: A total of 50,148 patients were identified, of which 165 (0.3%) indicated the use of NIF and 49,983 (99.7%) did not. After propensity score matching, 990 patients were included (NIF cohort: 165; NoNIF cohort: 825). Of the 165 NIF patients, 87 were robotic-assisted and 78 were conventional laparoscopy. Of the 825 NoNIF patients, 136 were robotic-assisted and 689 were conventional laparoscopy. Postindex inpatient readmission costs were significantly different between the NIF and NoNIF cohorts with the NIF cohort having the lowest 30- and 90-day postindex readmission costs. Postindex readmission costs were also significantly different across the 4 subgroups at 30 and 90 days, with the NIF-NoR group having the lowest postindex readmission costs (all P

Green economy is the way forward to achieve economic, social and environmental, sustainable development. However, to accelerate the transition to green economy, private sector companies need to understand the impact of imposing green polices and activities on the economy. Therefore, this paper examines the impact of green growth on future aggregate stock market returns on European stock exchanges. Using fixed effects model, the results show that green growth policies result in lower future aggregate stock market returns consistent with the investors’ perceived reduction in risk argument. The findings of this paper enhance our understanding of how transition to a more sustainable green economy could impact the aggregate return of financial markets. The results remain unchanged after estimating standard errors clustered by country, by year and by both country and year. However desirable it is to adopt a green economy, it is important to implement the right measures to support it sensitively, without imposing heavy costs that severely affect economic health.

Summary: Background: The Invasive Respiratory Infection Surveillance (IRIS) Consortium was established to assess the impact of the COVID-19 pandemic on invasive diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae. We aimed to analyse the incidence and distribution of these diseases during the first 2 years of the COVID-19 pandemic compared to the 2 years preceding the pandemic. Methods: For this prospective analysis, laboratories in 30 countries and territories representing five continents submitted surveillance data from Jan 1, 2018, to Jan 2, 2022, to private projects within databases in PubMLST. The impact of COVID-19 containment measures on the overall number of cases was analysed, and changes in disease distributions by patient age and serotype or group were examined. Interrupted time-series analyses were done to quantify the impact of pandemic response measures and their relaxation on disease rates, and autoregressive integrated moving average models were used to estimate effect sizes and forecast counterfactual trends by hemisphere. Findings: Overall, 116 841 cases were analysed: 76 481 in 2018–19, before the pandemic, and 40 360 in 2020–21, during the pandemic. During the pandemic there was a significant reduction in the risk of disease caused by S pneumoniae (risk ratio 0·47; 95% CI 0·40–0·55), H influenzae (0·51; 0·40–0·66) and N meningitidis (0·26; 0·21–0·31), while no significant changes were observed for S agalactiae (1·02; 0·75–1·40), which is not transmitted via the respiratory route. No major changes in the distribution of cases were observed when stratified by patient age or serotype or group. An estimated 36 289 (95% prediction interval 17 145–55 434) cases of invasive bacterial disease were averted during the first 2 years of the pandemic among IRIS-participating countries and territories. Interpretation: COVID-19 containment measures were associated with a sustained decrease in the incidence of invasive disease caused by S pneumoniae, H influenzae, and N meningitidis during the first 2 years of the pandemic, but cases began to increase in some countries towards the end of 2021 as pandemic restrictions were lifted. These IRIS data provide a better understanding of microbial transmission, will inform vaccine development and implementation, and can contribute to health-care service planning and provision of policies. Funding: Wellcome Trust, NIHR Oxford Biomedical Research Centre, Spanish Ministry of Science and Innovation, Korea Disease Control and Prevention Agency, Torsten Söderberg Foundation, Stockholm County Council, Swedish Research Council, German Federal Ministry of Health, Robert Koch Institute, Pfizer, Merck, and the Greek National Public Health Organization.

Summary: Delivery of pharmaceutical therapeutics to the inner ear to treat and prevent hearing loss is challenging. Systemic delivery is not effective as only a small fraction of the therapeutic agent reaches the inner ear. Invasive surgeries to inject through the round window membrane (RWM) or cochleostomy may cause damage to the inner ear. An alternative approach is to administer drugs into the middle ear using an intratympanic injection, with the drugs primarily passing through the RWM to the inner ear. However, the RWM is a barrier, only permeable to a small number of molecules. To study and enhance the RWM permeability, we developed an ex vivo porcine RWM model, similar in structure and thickness to the human RWM. The model is viable for days, and drug passage can be measured at multiple time points. This model provides a straightforward approach to developing effective and non-invasive delivery methods to the inner ear.

Background: Nursing home (NH) social workers face many challenges in meeting the psychosocial needs of residents while balancing their own well-being needs. Methods: This study employed a cross-sectional survey of NH social workers via social media and professional networks about their coping strategies during COVID-19. Open-ended responses were analyzed qualitatively using the rigorous and accelerated data reduction technique (RADaR). Results: The study included a sample of 63 (N = 63) NH social workers. Four themes defined ways the in which NH social workers coped with stress during COVID-19, including relying on friends and family, mindfulness and spirituality/religion, self-care strategies, and setting boundaries at work. Conclusion: These techniques appear to be effective; however there remains a need for institutional programs and policies to provide the time and space to holistically support coping in NH social workers and to prevent burnout and turnover, particularly during times of crisis.

Abstract Background Theoretically, artificial intelligence can provide an accurate automatic solution to measure right ventricular (RV) ejection fraction (RVEF) from cardiovascular magnetic resonance (CMR) images, despite the complex RV geometry. However, in our recent study, commercially available deep learning (DL) algorithms for RVEF quantification performed poorly in some patients. The current study was designed to test the hypothesis that quantification of RV function could be improved in these patients by using more diverse CMR datasets in addition to domain-specific quantitative performance evaluation metrics during the cross-validation phase of DL algorithm development. Methods We identified 100 patients from our prior study who had the largest differences between manually measured and automated RVEF values. Automated RVEF measurements were performed using the original version of the algorithm (DL1), an updated version (DL2) developed from a dataset that included a wider range of RV pathology and validated using multiple domain-specific quantitative performance evaluation metrics, and conventional methodology performed by a core laboratory (CORE). Each of the DL-RVEF approaches was compared against CORE-RVEF reference values using linear regression and Bland–Altman analyses. Additionally, RVEF values were classified into 3 categories: ≤ 35%, 35–50%, and ≥ 50%. Agreement between RVEF classifications made by the DL approaches and the CORE measurements was tested. Results CORE-RVEF and DL-RVEFs were obtained in all patients (feasibility of 100%). DL2-RVEF correlated with CORE-RVEF better than DL1-RVEF (r = 0.87 vs. r = 0.42), with narrower limits of agreement. As a result, DL2 algorithm also showed increasing accuracy from 0.53 to 0.80 for categorizing RV function. Conclusions The use of a new DL algorithm cross-validated on a dataset with a wide range of RV pathology using multiple domain-specific metrics resulted in a considerable improvement in the accuracy of automated RVEF measurements. This improvement was demonstrated in patients whose images were the most challenging and resulted in the largest RVEF errors. These findings underscore the critical importance of this strategy in the development of DL approaches for automated CMR measurements.

Objective: To determine whether continuous positive airway pressure (CPAP) adherence reduces health care–related costs or use in patients with obstructive sleep apnea (OSA) and comorbid cardiovascular disease (CVD). Patients: A total of 23 million patients with CVD were identified in the Medicare fee-for-service database. Of the 65,198 who completed a sleep study between January 2016 and September 2018, 55,125 were diagnosed as having OSA and 1758 were identified in the 5% Medicare durable medical equipment (DME) database. Methods: Patients with DME claims were categorized as adherent (AD, treatment evidenced ≥91 days after CPAP initiation; n=614) or nonadherent (nAD, n=242) to CPAP therapy. In addition, 9881 individuals with CVD who were not diagnosed as having OSA after sleep testing and without CPAP initiation were included as control patients. Propensity score matching balanced the groups for age, sex, and comorbidities (eg, diabetes mellitus), resulting in 241 participants per cohort. Dependent variables included total episode-of-care, inpatient, outpatient, skilled nursing, home health, and DME costs across 12 months. Results: Total episode-of-care costs of AD participants ($6825) were lower than those of nAD ($11,312; P

Background & Aims: Single-cell transcriptomics offer unprecedented resolution of tissue function at the cellular level, yet studies analyzing healthy adult human small intestine and colon are sparse. Here, we present single-cell transcriptomics covering the duodenum, jejunum, ileum, and ascending, transverse, and descending colon from 3 human beings. Methods: A total of 12,590 single epithelial cells from 3 independently processed organ donors were evaluated for organ-specific lineage biomarkers, differentially regulated genes, receptors, and drug targets. Analyses focused on intrinsic cell properties and their capacity for response to extrinsic signals along the gut axis across different human beings. Results: Cells were assigned to 25 epithelial lineage clusters. Multiple accepted intestinal stem cell markers do not specifically mark all human intestinal stem cells. Lysozyme expression is not unique to human Paneth cells, and Paneth cells lack expression of expected niche factors. Bestrophin 4 (BEST4)+ cells express Neuropeptide Y (NPY) and show maturational differences between the small intestine and colon. Tuft cells possess a broad ability to interact with the innate and adaptive immune systems through previously unreported receptors. Some classes of mucins, hormones, cell junctions, and nutrient absorption genes show unappreciated regional expression differences across lineages. The differential expression of receptors and drug targets across lineages show biological variation and the potential for variegated responses. Conclusions: Our study identifies novel lineage marker genes, covers regional differences, shows important differences between mouse and human gut epithelium, and reveals insight into how the epithelium responds to the environment and drugs. This comprehensive cell atlas of the healthy adult human intestinal epithelium resolves likely functional differences across anatomic regions along the gastrointestinal tract and advances our understanding of human intestinal physiology.

Individuals with acute and chronic traumatic brain injury (TBI) are associated with unique white matter (WM) structural abnormalities, including fractional anisotropy (FA) differences. Our research group previously used FA as a feature in a linear support vector machine (SVM) pattern classifier, observing high classification between individuals with and without acute TBI (i.e., an area under the curve [AUC] value of 75.50%). However, it is not known whether FA could similarly classify between individuals with and without history of chronic TBI. Here, we attempted to replicate our previous work with a new sample, investigating whether FA could similarly classify between incarcerated men with (n = 80) and without (n = 80) self-reported history of chronic TBI. Additionally, given limitations associated with FA, including underestimation of FA values in WM tracts containing crossing fibers, we extended upon our previous study by incorporating neurite orientation dispersion and density imaging (NODDI) metrics, including orientation dispersion (ODI) and isotropic volume (Viso). A linear SVM based classification approach, similar to our previous study, was incorporated here to classify between individuals with and without self-reported chronic TBI using FA and NODDI metrics as separate features. Overall classification rates were similar when incorporating FA and NODDI ODI metrics as features (AUC: 82.50%). Additionally, NODDI-based metrics provided the highest sensitivity (ODI: 85.00%) and specificity (Viso: 82.50%) rates. The current study serves as a replication and extension of our previous study, observing that multiple diffusion MRI metrics can reliably classify between individuals with and without self-reported history of chronic TBI.

Purpose: To describe qualitative and quantitative longitudinal changes in dopamine transporter uptake (DaT) scan findings in progressive apraxia of speech (PAOS) patients. Methods: DaTQUANT software was used to quantify uptake in the left and right caudate and putamen in DaT scans of 39 patients with PAOS, 19 with repeat scans. Clinical radiologic impressions were used as the gold standard for evaluating whether quantitative measures (z-score of left and right putamen and caudate uptake) aligned with gestalt impressions of DaT abnormalities and clinical impairments, cross-sectionally. Measures at first and last available DaT were used to evaluate change over time and the influence of qualitative abnormality at first visit on change over time. Results: Cross-sectionally, 16/39 patients had abnormal DaT scans on visual read, with differences in all quantitative DaT measures between those with (ab)normal scans, but without differences in any clinical measures (apraxia of speech, aphasia, or parkinsonism). Three patients that had normal DaT scans at baseline were read as abnormal at subsequent visits, with coinciding change in quantitative measures. At the group level, across the 19 patients with repeat imaging, no statistical change in left or right caudate or putamen scores was observed despite progression of clinical indices. Abnormality at first visit did not statistically influence the rate of change over time, although trends were observed. Conclusions: Approximately 40–50% of patients with PAOS have or will develop DaT scans that may be visually read as abnormal. Quantitative measures of DaT match visual reads cross-sectionally, but may not map to clinical progression, including of parkinsonism, observed in these patients.

Purpose: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder affecting the planning or programming of speech. Little is known about its magnetic susceptibility profiles indicative of biological processes such as iron deposition and demyelination. This study aims to clarify (1) the pattern of susceptibility in PAOS patients, (2) the susceptibility differences between the phonetic (characterized by predominance of distorted sound substitutions and additions) and prosodic (characterized by predominance of slow speech rate and segmentation) subtypes of PAOS, and (3) the relationships between susceptibility and symptom severity. Methods: Twenty patients with PAOS (nine phonetic and eleven prosodic subtypes) were prospectively recruited and underwent a 3 Tesla MRI scan. They also underwent detailed speech, language, and neurological evaluations. Quantitative susceptibility maps (QSM) were reconstructed from multi-echo gradient echo MRI images. Region of interest analysis was conducted to estimate susceptibility coefficients in several subcortical and frontal regions. We compared susceptibility values between PAOS and an age-matched control group and performed a correlation analysis between susceptibilities and an apraxia of speech rating scale (ASRS) phonetic and prosodic feature ratings. Results: The magnetic susceptibility of PAOS was statistically greater than that of controls in subcortical regions (left putamen, left red nucleus, and right dentate nucleus) (p

Individuals with history of childhood trauma are characterized by aberrant resting-state limbic and paralimbic functional network connectivity. However, it is unclear whether specific subtypes of trauma (i.e., experienced vs observed or community) showcase differential effects. This study examined whether subtypes of childhood trauma (assessed via the Trauma Checklist [TCL] 2.0) were associated with aberrant intra-network amplitude of fluctuations and connectivity (i.e., functional coherence within a network), and inter-network connectivity across resting-state networks among incarcerated juvenile males (n = 179). Subtypes of trauma were established via principal component analysis of the TCL 2.0 and resting-state networks were identified by applying group independent component analysis to resting-state fMRI scans. We tested the association of subtypes of childhood trauma (i.e., TCL Factor 1 measuring experienced trauma and TCL Factor 2 assessing community trauma), and TCL Total scores to the aforementioned functional connectivity measures. TCL Factor 2 scores were associated with increased high-frequency fluctuations and increased intra-network connectivity in cognitive control, auditory, and sensorimotor networks, occurring primarily in paralimbic regions. TCL Total scores exhibited similar neurobiological patterns to TCL Factor 2 scores (with the addition of aberrant intra-network connectivity in visual networks), and no significant associations were found for TCL Factor 1. Consistent with previous analyses of community samples, our results suggest that childhood trauma among incarcerated juvenile males is associated with aberrant intra-network amplitude of fluctuations and connectivity across multiple networks including predominately paralimbic regions. Our results highlight the importance of accounting for traumatic loss, observed trauma, and community trauma in assessing neurobiological aberrances associated with adverse experiences in childhood, as well as the value of trained-rater trauma assessments compared to self-report.

Background: Bottled water (BW) consumption in the United States and globally has increased amidst heightened concern about environmental contaminant exposures and health risks in drinking water supplies, despite a paucity of directly comparable, environmentally-relevant contaminant exposure data for BW. This study provides insight into exposures and cumulative risks to human health from inorganic/organic/microbial contaminants in BW. Methods: BW from 30 total domestic US (23) and imported (7) sources, including purified tapwater (7) and spring water (23), were analyzed for 3 field parameters, 53 inorganics, 465 organics, 14 microbial metrics, and in vitro estrogen receptor (ER) bioactivity. Health-benchmark-weighted cumulative hazard indices and ratios of organic-contaminant in vitro exposure-activity cutoffs were assessed for detected regulated and unregulated inorganic and organic contaminants. Results: 48 inorganics and 45 organics were detected in sampled BW. No enforceable chemical quality standards were exceeded, but several inorganic and organic contaminants with maximum contaminant level goal(s) (MCLG) of zero (no known safe level of exposure to vulnerable sub-populations) were detected. Among these, arsenic, lead, and uranium were detected in 67 %, 17 %, and 57 % of BW, respectively, almost exclusively in spring-sourced samples not treated by advanced filtration. Organic MCLG exceedances included frequent detections of disinfection byproducts (DBP) in tapwater-sourced BW and sporadic detections of DBP and volatile organic chemicals in BW sourced from tapwater and springs. Precautionary health-based screening levels were exceeded frequently and attributed primarily to DBP in tapwater-sourced BW and co-occurring inorganic and organic contaminants in spring-sourced BW. Conclusion: The results indicate that simultaneous exposures to multiple drinking-water contaminants of potential human-health concern are common in BW. Improved understandings of human exposures based on more environmentally realistic and directly comparable point-of-use exposure characterizations, like this BW study, are essential to public health because drinking water is a biological necessity and, consequently, a high-vulnerability vector for human contaminant exposures.

Abstract Background Mapping of left ventricular (LV) native T1 is a promising non-invasive, non-contrast imaging biomarker. Native myocardial T1 times are prolonged in patients requiring dialysis, but there are concerns that the dialysis process and fluctuating fluid status may confound results in this population. We aimed to assess the changes in cardiac parameters on 3T cardiovascular magnetic resonance (CMR) before and after haemodialysis, with a specific focus on native T1 mapping. Methods This is a single centre, prospective observational study in which maintenance haemodialysis patients underwent CMR before and after dialysis (both scans within 24 h). Weight measurement, bio-impedance body composition monitoring, haemodialysis details and fluid intake were recorded. CMR protocol included cine imaging and mapping native T1 and T2. Results Twenty-six participants (16 male, 65 ± 9 years) were included in the analysis. The median net ultrafiltration volume on dialysis was 2.3 L (IQR 1.8, 2.5), resulting in a median weight reduction at post-dialysis scan of 1.35 kg (IQR 1.0, 1.9), with a median reduction in over-hydration (as measured by bioimpedance) of 0.75 L (IQR 0.5, 1.4). Significant reductions were observed in LV end-diastolic volume (− 25 ml, p = 0.002), LV stroke volume (− 13 ml, p = 0.007), global T1 (21 ms, p = 0.02), global T2 (− 1.2 ms, p = 0.02) following dialysis. There was no change in LV mass (p = 0.35), LV ejection fraction (p = 0.13) or global longitudinal strain (p = 0.22). On linear regression there was no association between baseline over-hydration (as defined by bioimpedance) and global native T1 or global T2, nor was there an association between the change in over-hydration and the change in these parameters. Conclusions Acute changes in cardiac volumes and myocardial native T1 are detectable on 3T CMR following haemodialysis with fluid removal. The reduction in global T1 suggests that the abnormal native T1 observed in patients on haemodialysis is not entirely due to myocardial fibrosis.

Summary: The relevance of minor transcription start sites in broad promoters is not well understood. We have studied AGAP2 expression in prostate cancer and chronic myeloid leukemia (CML), showing transcription is initiated from alternative transcription start sites (TSSs) within a single TSS cluster, producing cancer-type-specific AGAP2 mRNAs with small differences in their 5′ UTR length. Interestingly, in the CML cell lines where the 5′ UTR is longer, AGAP2 protein levels are lower. We demonstrate that the selection of an upstream TSS involved the formation of a G quadruplex in the 5′ UTR, decreasing polysome formation. After developing a bioinformatics pipeline to query data from the FANTOM project and the NCl-60 human tumor cell lines screen, we found HK1 expression can also be regulated by the same mechanism. Overall, we present compelling data supporting TSS selection within a TSS cluster play a role in protein expression and should not be ignored.

The COVID-19 pandemic required people to navigate lockdowns and unfamiliar restrictions for the first time. It is known that situations characterised by uncontrollability and novelty heighten the physiological response to stress. The data presented here was collected as part of an experimental stress study and offered an opportunity to compare cortisol levels upon arrival to the lab before and after the first UK lockdown, when students had to navigate novel health and safety restrictions on campus.Participants (n = 152) were students who took part in an experiment designed to measure salivary cortisol levels as a response to a stress task. All provided a baseline cortisol sample after arriving to the lab but before the experimental task. Pre-lockdown participants (n = 72) were familiar with the campus rules whereas post-lockdown participants (n = 80) had to adhere to novel restrictions, including health questionnaires, PPE and social distancing.The post-lockdown sample had significantly higher levels of baseline cortisol, cortisol output (AUCg) and cortisol response (AUCi) than the pre-lockdown group. This effect remained significant even after controlling for sample characteristics.These findings suggest that navigating new restrictions may lead to heightened levels of anticipatory stress even if there is no difference in recent general mental health before and after the lockdown.

Rationale & Objective: To evaluate progression patterns and associated economic outcomes, using estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) based on the Kidney Disease: Improving Global Outcomes (KDIGO) risk categories, among patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). Study Design: Patients with T2D and moderate- or high-risk CKD were selected from the Optum electronic health records database (January 2007-December 2019). Progression patterns and post-progression economic outcomes were assessed. Setting & Participants: Adults with T2D and CKD in clinical settings. Predictor: Baseline KDIGO risk categories. Outcomes: Progression to a more severe KDIGO risk category; healthcare resource utilization and medical costs. Analytical Approach: Progression probability was estimated using cumulative incidence. Healthcare resource utilization and costs were compared across progression groups. Results: Of 269,187 patients (mean age 65.6 years) with T2D and CKD of moderate or high baseline risk, 18.9% progressed to the very high-risk category within 5 years. Among moderate-risk patients, 17.8% of CKD stage G1-A2, 44.0% of stage G2-A2, and 61.3% of stage G3a-A1 patients progressed to a higher KDIGO risk category. Among high-risk patients, 63.9% of stage G3b-A1/G3a-A2 and 56.0% of stage G2-A3 patients progressed to very high risk. Within the same eGFR stage, a higher UACR stage was associated with 4- to 7-times higher risk of progressing to very high risk and faster eGFR decline. Nonprogressors had lower annual medical costs ($16,924) than patients who progressed from moderate risk to high risk ($22,117, P < 0.05), from high risk to very high risk ($32,204, P < 0.05), and from moderate risk to very high risk ($35,092, P < 0.05). Limitations: Infrequent lab testing might have caused lags in identifying progression; medical costs were calculated using unit costs. Conclusions: Patients with T2D and CKD of moderate or high risk per KDIGO risk categories had high probabilities of progression, incurring a substantial economic burden. The results highlight the value of UACR in CKD management.

Background: The COVID-19 pandemic led to cancelation of all elective surgeries for a time period in the vast majority of the United States. We compiled a questionnaire to determine the physical and mental toll of this delay on elective total joint arthroplasty patients. Methods: All patients whose primary or revision total hip or knee arthroplasty was canceled because of the COVID-19 pandemic at a large academic-private practice were identified. An 11-question survey was administered to these patients via email. All data were deidentified and stored in a REDCAP database. Results: Of 367 total patients identified, 113 responded to the survey. Seventy-seven percent of patients had their surgery postponed at least 5 weeks, and 20% were delayed longer than 12 weeks. Forty-one percent of patients reported an average visual analog scale pain score greater than 7.5. Forty percent of respondents experienced increased anxiety during the delay. Thirty-four percent of patients felt their surgery was not elective. Sixteen percent experienced a fall during the delay, and 1 patient sustained a hip fracture. Level of pain reported was significantly associated with negative emotions, negative effects of delay, and whether patients felt their surgery was indeed elective. Seventy-six percent reported trust in their surgeon’s judgment regarding appropriate timing of surgery. Communication was listed as the number one way in which patients felt their surgeon could have improved during this time. Conclusion: Surgical delay due to the COVID-19 pandemic resulted in increased pain and anxiety for many total joint arthroplasty patients. While most patients maintained trust in their surgeon during the delay, methods to improve communication may benefit the patient experience in future delays. Level of Evidence: Level II.

Previous studies indicate that cyanobacterial harmful algal bloom (cyanoHAB) frequency, extent, and magnitude have increased globally over the past few decades. However, little quantitative capability is available to assess these metrics of cyanoHABs across broad geographic scales and at regular intervals. Here, the spatial extent was quantified from a cyanobacteria algorithm applied to two European Space Agency satellite platforms—the MEdium Resolution Imaging Spectrometer (MERIS) onboard Envisat and the Ocean and Land Colour Instrument (OLCI) onboard Sentinel-3. CyanoHAB spatial extent was defined for each geographic area as the percentage of valid satellite pixels that exhibited cyanobacteria above the detection limit of the satellite sensor. This study quantified cyanoHAB spatial extent for over 2,000 large lakes and reservoirs across the contiguous United States (CONUS) during two time periods: 2008–2011 via MERIS and 2017–2020 via OLCI when cloud-, ice-, and snow-free imagery was available. Approximately 56% of resolvable lakes were glaciated, 13% were headwater, isolated, or terminal lakes, and the rest were primarily drainage lakes. Results were summarized at national-, regional-, state-, and lake-scales, where regions were defined as nine climate regions which represent climatically consistent states. As measured by satellite, changes in national cyanoHAB extent did have a strong increase of 6.9% from 2017 to 2020 (|Kendall’s tau (τ)| = 0.56; gamma (γ) = 2.87 years), but had negligible change (|τ| = 0.03) from 2008 to 2011. Two of the nine regions had moderate (0.3 ≤ |τ| < 0.5) increases in spatial extent from 2017 to 2020, and eight of nine regions had negligible (|τ| < 0.2) change from 2008 to 2011. Twelve states had a strong or moderate increase from 2017 to 2020 (|τ| ≥ 0.3), while only one state had a moderate increase and two states had a moderate decrease from 2008 to 2011. A decrease, or no change, in cyanoHAB spatial extent did not indicate a lack of issues related to cyanoHABs. Sensitivity results of randomly omitted daily CONUS scenes confirm that even with reduced data availability during a short four-year temporal assessment, the direction and strength of the changes in spatial extent remained consistent. We present the first set of national maps of lake cyanoHAB spatial extent across CONUS and demonstrate an approach for quantifying past and future changes at multiple spatial scales. Results presented here provide water quality managers information regarding current cyanoHAB spatial extent and quantify rates of change.

Background: Insulin use may be a better predictor of stroke risk and morbidity and mortality than diabetes in patients with atrial fibrillation (AF). Objectives: Determine if the increased risk of stroke observed in patients with AF and diabetes is restricted to those treated with insulin. Methods: We analyzed the association between diabetes and treatment and the occurrence of stroke/systemic embolism, myocardial infarction (MI), all-cause death, vascular death, composite outcomes, and bleeding risk in the ROCKET AF trial. Results: In a cohort of 14,264 patients, there were 40.3% (n = 5746) with diabetes, 5.9% (n = 842) on insulin, 18.9% (n = 2697) on oral medications, and 11.9% (n = 1703) diet-controlled. Compared to those without diabetes, patients with non–insulin-treated diabetes had increased risks of stroke (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.06–1.68), MI (HR 1.64, 95% CI 1.17–2.30), all-cause death (HR 1.26, 95% CI 1.08–1.46), vascular death (HR 1.33, 95% CI 1.11–1.60), and composite outcomes (HR 1.37, 95% CI 1.18–1.157). Patients with insulin-treated diabetes had a significantly higher risk of MI (HR 2.31, 95% CI 1.33–4.01) and composite outcomes (HR 1.57, 95% CI 1.19–2.08) compared to those without diabetes. There were no significant differences between insulin-treated and non–insulin-treated diabetes for any outcome. Conclusion: Among patients with AF and diabetes, there were no significant differences in outcomes in insulin-treated diabetes compared to non–insulin-treated diabetes.

Background: It is estimated that 20–30% of ginseng crops in Canada are lost to root rot each harvest. This disease is commonly caused by fungal infection with Ilyonectria, previously known as Cylindrocarpon. Previous reports have linked the virulence of fungal disease to the production of siderophores, a class of small-molecule iron chelators. However, these siderophores have not been identified in Ilyonectria. Methods: High-resolution LC–MS/MS was used to screen Ilyonectria and Cylindrocarpon strain extracts for secondary metabolite production. These strains were also tested for their ability to cause root rot in American ginseng and categorized as virulent or avirulent. The differences in detected metabolites between the virulent and avirulent strains were compared with a focus on siderophores. Results: For the first time, a siderophore N,N′,N″-triacetylfusarinine C (TAFC) has been identified in Ilyonectria, and it appears to be linked to disease virulence. Siderophore production was suppressed as the concentration of iron increased, which is in agreement with previous reports. Conclusion: The identification of the siderophore produced by Ilyonectria gives us further insight into the root rot disease that heavily affects ginseng crop yields. This research identifies a molecular pathway previously unknown for ginseng root rot and could lead to new disease treatment options.

Standardized phantoms and test methods are needed to accelerate clinical translation of emerging photoacoustic imaging (PAI) devices. Evaluating object detectability in PAI is challenging due to variations in target morphology and artifacts including boundary buildup. Here we introduce breast fat and parenchyma tissue-mimicking materials based on emulsions of silicone oil and ethylene glycol in polyacrylamide hydrogel. 3D-printed molds were used to fabricate solid target inclusions that produced more filled-in appearance than traditional PAI phantoms. Phantoms were used to assess understudied image quality characteristics (IQCs) of three PAI systems. Object detectability was characterized vs. target diameter, absorption coefficient, and depth. Boundary buildup was quantified by target core/boundary ratio, which was higher in transducers with lower center frequency. Target diameter measurement accuracy was also size-dependent and improved with increasing transducer frequency. These phantoms enable evaluation of multiple key IQCs and may support development of comprehensive standardized test methods for PAI devices.

To broaden the scope of contaminants monitored in human-impacted riverine systems, water, sediment, and treated wastewater effluent were analyzed using receptor-based cell assays that provide an integrated response to chemicals based on their mode of biological activity. Samples were collected from three California (USA) watersheds with varying degrees of urbanization and discharge from municipal wastewater treatment plants (WWTPs). To complement cell assay results, samples were also analyzed for a suite of contaminants of emerging concern (CECs) using gas and liquid chromatography-mass spectrometry (GC- and LC-MS/MS). For most water and sediment samples, bioassay equivalent concentrations for estrogen and glucocorticoid receptor assays (ER- and GR-BEQs, respectively) were near or below reporting limits. Measured CEC concentrations compared to monitoring trigger values established by a science advisory panel indicated minimal to moderate concern in water but suggested that select pesticides (pyrethroids and fipronil) had accumulated to levels of greater concern in river sediments. Integrating robust, standardized bioanalytical tools such as the ER and GR assays utilized in this study into existing chemical-specific monitoring and assessment efforts will enhance future CEC monitoring efforts in impacted riverine systems and coastal watersheds.

Purpose: The dosimetric parameters used clinically to reduce the likelihood of radiation pneumonitis (RP) for lung cancer radiation therapy have traditionally been V20Gy ≤ 30% to 35% and mean lung dose ≤ 20 to 23 Gy; however, these parameters are derived based on studies from photon therapy. The purpose of this study is to evaluate whether such dosimetric predictors for RP are applicable for locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with proton therapy. Methods and Materials: In the study, 160 (78 photon, 82 proton) patients with LA-NSCLC treated with chemoradiotherapy between 2011 and 2016 were retrospectively identified. Forty (20 photon, 20 proton) patients exhibited grade ≥2 RP after therapy. Dose volume histograms for the uninvolved lung were extracted for each patient. The percent lung volumes receiving above various dose levels were obtained in addition to V20Gy and Dmean. These dosimetric parameters and patient characteristics were evaluated with univariate and multivariate logistic regression tests. Receiver operating characteristic curves were generated to obtain the optimal dosimetric constraints through analyzing RP and non-RP sensitivity and specificity values. Results: The multivariate analysis showed V40Gy and Dmean to be statistically significant for proton and photon patients, respectively. V35Gy to V50Gy were strongly correlated to V40Gy for proton patients. Based on the receiver operating characteristic curves, V35Gy to V50Gy had the highest area under the curve compared with other dose levels for proton patients. A potential dosimetric constraint for RP predictor in proton patients is V40Gy ≤ 23%. Conclusions: In addition to V20Gy and Dmean, the lung volume receiving higher doses, such as V40Gy, may be used as an additional indicator for RP in LA-NSCLC patients treated with proton therapy.

Background and Purpose: Radiation esophagitis is a clinically important toxicity seen with treatment for locally-advanced non-small cell lung cancer. There is considerable disagreement among prior studies in identifying predictors of radiation esophagitis. We apply machine learning algorithms to identify factors contributing to the development of radiation esophagitis to uncover previously unidentified criteria and more robust dosimetric factors. Materials and Methods: We used machine learning approaches to identify predictors of grade ≥ 3 radiation esophagitis in a cohort of 202 consecutive locally-advanced non-small cell lung cancer patients treated with definitive chemoradiation from 2008 to 2016. We evaluated 35 clinical features per patient grouped into risk factors, comorbidities, imaging, stage, histology, radiotherapy, chemotherapy and dosimetry. Univariate and multivariate analyses were performed using a panel of 11 machine learning algorithms combined with predictive power assessments. Results: All patients were treated to a median dose of 66.6 Gy at 1.8 Gy per fraction using photon (89.6%) and proton (10.4%) beam therapy, most often with concurrent chemotherapy (86.6%). 11.4% of patients developed grade ≥ 3 radiation esophagitis. On univariate analysis, no individual feature was found to predict radiation esophagitis (AUC range 0.45–0.55, p ≥ 0.07). In multivariate analysis, all machine learning algorithms exhibited poor predictive performance (AUC range 0.46–0.56, p ≥ 0.07). Conclusions: Contemporary machine learning algorithms applied to our modern, relatively large institutional cohort could not identify any reliable predictors of grade ≥ 3 radiation esophagitis. Additional patients are needed, and novel patient-specific and treatment characteristics should be investigated to develop clinically meaningful methods to mitigate this survival altering toxicity. Keywords: Radiation esophagitis, Machine learning, Non-small cell lung cancer, Chemoradiation, Radiation-induced toxicity, Intensity-modulated radiation therapy, Proton beam therapy

Background & Aims: Despite achieving endoscopic remission, more than 20% of inflammatory bowel disease patients experience chronic abdominal pain. These patients have increased rectal transient receptor potential vanilloid-1 receptor (TRPV1) expression, a key transducer of inflammatory pain. Because inflammatory bowel disease patients in remission exhibit dysbiosis and microbial manipulation alters TRPV1 function, our goal was to examine whether microbial perturbation modulated transient receptor potential function in a mouse model. Methods: Mice were given dextran sodium sulfate (DSS) to induce colitis and were allowed to recover. The microbiome was perturbed by using antibiotics as well as fecal microbial transplant (FMT). Visceral and somatic sensitivity were assessed by recording visceromotor responses to colorectal distention and using hot plate/automated Von Frey tests, respectively. Calcium imaging of isolated dorsal root ganglia neurons was used as an in vitro correlate of nociception. The microbiome composition was evaluated via 16S rRNA gene variable region V4 amplicon sequencing, whereas fecal short-chain fatty acids (SCFAs) were assessed by using targeted mass spectrometry. Results: Postinflammatory DSS mice developed visceral and somatic hyperalgesia. Antibiotic administration during DSS recovery induced visceral, but not somatic, hyperalgesia independent of inflammation. FMT of postinflammatory DSS stool into antibiotic-treated mice increased visceral hypersensitivity, whereas FMT of control stool reversed antibiotics’ sensitizing effects. Postinflammatory mice exhibited both increased SCFA-producing species and fecal acetate/butyrate content compared with controls. Capsaicin-evoked calcium responses were increased in naive dorsal root ganglion neurons incubated with both sodium butyrate/propionate alone and with colonic supernatants derived from postinflammatory mice. Conclusions: The microbiome plays a central role in postinflammatory visceral hypersensitivity. Microbial-derived SCFAs can sensitize nociceptive neurons and may contribute to the pathogenesis of postinflammatory visceral pain.

Summary: Elimination of cancerous cells by the immune system is an important mechanism of protection from cancer, however, its effectiveness can be reduced owing to development of resistance and evasion. To understand the systemic immune response in advanced untreated primary colorectal cancer, we analyze immune subtypes and immune evasion via neoantigen-related mechanisms. We identify a distinctive cancer subtype characterized by immune evasion and very poor overall survival. This subtype has less clonal highly expressed neoantigens and high chromosomal instability, resulting in adaptive immune resistance mediated by the immune checkpoint molecules and neoantigen presentation disorders. We also observe that neoantigen depletion caused by immunoediting and high clonal neoantigen load are correlated with a good overall survival. Our results indicate that the status of the tumor microenvironment and neoantigen composition are promising new prognostic biomarkers with potential relevance for treatment plan decisions in advanced CRC.

The introduction of coronavirus 2019 (COVID-19) vaccination has been an integral force in stopping the spread of COVID-19 across the globe. While reported side effects of vaccination have predominantly been mild, in the last year reports have emerged of myocarditis following the BNT162b2 (Pfizer-BioNtech) and mRNA-1273 (Moderna) vaccinations. The adolescent and young adult population have been the population most reported, with over 1000 cases under review by the Centers for Disease Control (CDC) since April 2021. Here we report a case of a previously healthy 21-year-old male who developed Multisystem Inflammatory Syndrome in Adults (MIS-A) and following the second dose of the Pfizer-BioNtech vaccine. The young male initially presented with fever, leukocytosis with high neutrophil-lymphocyte ratio, severe cardiac illness, and positive COVID-19 nucleocapsid serology, consistent with MIS-A diagnosis. His case was complicated by cardiogenic shock, requiring brief venoarterial extracorporeal membrane oxygenation (VA-ECMO) support. While this report does not detract from the overwhelming benefit of vaccination from COVID-19, clinicians should be aware of this possible relationship in the future.

Dolutegravir/Lamivudina (DTG / 3TC) é um regime completo de 2 medicamentos (2DR) para o tratamento do HIV-1. A eficácia virológica não inferior foi comprovada ao longo de 3 anos em pessoas virgens de tratamento PARA HIV e 2 anos em um ambiente de troca estável. TANGO, um estudo randomizado, aberto e de não inferioridade, avalia a eficácia e a segurança da mudança para DTG/3TC em adultos virologicamente suprimidos (> 6 meses, sem falha virológica anterior, sem resistência maior a INI ou ITRN) vs permanecer em um regime baseado em tenofovir alafenamida (TBR) de 3 ou 4 medicamentos, estratificado pela 3ª classe de agente basal. As análises da semana 144 avaliaram a não inferioridade (margem de 4% para falha virológica e 8% para sucesso virológico; análise de snapshot, intenção de tratar na população exposta [ITT-E]). De 741 participantes randomizados/expostos (DTG/3TC, 369; TBR, 372), a maioria entrou no estudo com elvitegravir/cobicistate (66%). Na semana 144, a mudança para DTG/3TC foi não inferior à continuação da TBR (falha virológica snapshot, ITT-E): 0,3% vs 1,3%; diferença ajustada (IC 95%): -1,1% (-2,4%, 0,2%) e superior à TBR na análise por protocolo: 0% vs 1,1%; diferença ajustada: -1,1% (-2,3%, -0,0%); p = 0,044 (bilateral). O sucesso virológico por snapshot foi alto em ambos os braços, demonstrando não inferioridade (DTG/3TC, 85,9% vs TBR, 81,7%; diferença ajustada [IC de 95%]: 4,2% [-1,1%, 9,5%]). Nenhum participante no DTG/3TC e 3 (0,8%) no TBR preencheram os critérios de retirada por falha virológica confirmada sem resistência observada. Nenhum participante em DTG/3TC e 6 (1,6%) em TBR descontinuaram por falta de eficácia. As taxas gerais de eventos adversos foram semelhantes entre os braços (DTG/3TC, 91%; TBR, 90%). Colesterol total (CT), colesterol LDL e triglicerídeos melhoraram com DTG/3TC, colesterol HDL melhorou com TBR, sem diferença na razão TC/HDL entre os braços. As alterações nos biomarcadores renais foram semelhantes entre os braços. A alteração média ajustada da linha de base no peso foi de 2,2 kg com DTG/3TC e 1,7 kg com TBR, e a proporção de participantes com aumento de peso ≥10% foi semelhante (DTG / 3TC, 13%; TBR, 12%). Mudar para DTG/3TC de um TBR de 3 ou 4 medicamentos resultou em eficácia elevada e não inferior, sem falhas virológicas confirmadas e boa tolerabilidade ao longo de 3 anos de tratamento. DTG/3TC é uma opção robusta com eficácia durável, boa segurança e tolerabilidade e uma alta barreira à resistência.

Transactive response DNA-binding protein of ∼43 kDa (TDP-43), a primary pathologic substrate in tau-negative frontotemporal lobar degeneration (FTLD), is also often found in the brains of elderly individuals without FTLD and is a key player in the process of neurodegeneration in brains with and without FTLD. It is unknown how rates and trajectories of TDP-43-associated brain atrophy compare between these two groups. Additionally, non-FTLD TDP-43 inclusions are not homogeneous and can be divided into two morphologic types: type-α and neurofibrillary tangle-associated type-β. Therefore, we explored whether neurodegeneration also varies due to the morphologic type. In this longitudinal retrospective study of 293 patients with 843 MRI scans spanning over ∼10 years, we used a Bayesian hierarchical linear model to quantify similarities and differences between the non-FTLD TDP-43 (type-α/type-β) and FTLD-TDP (n = 68) in both regional volume at various timepoints before death and annualized rate of atrophy. Since Alzheimer’s disease (AD) is a frequent co-pathology in non-FTLD TDP-43, we further divided types α/β based on presence/absence of intermediate-high likelihood AD: AD-TDP type-β (n = 90), AD-TDP type-α (n = 104), and Pure-TDP (n = 31, all type-α). FTLD-TDP was associated with faster atrophy rates in the inferior temporal lobe and temporal pole compared to all non-FTLD TDP-43 groups. The atrophy rate in the frontal lobe was modulated by age with younger FTLD-TDP having the fastest rates. Older FTLD-TDP showed a limbic predominant pattern of neurodegeneration. AD-TDP type-α showed faster rates of hippocampal atrophy and smaller volumes of amygdala, temporal pole, and inferior temporal lobe compared to AD-TDP type-β. Pure-TDP was associated with slowest rates and less atrophy in all brain regions. The results suggest that there are differences and similarities in longitudinal brain volume loss between FTLD-TDP and non-FTLD TDP-43. Within FTLD-TDP age plays a role in which brain regions are the most affected. Additionally, brain atrophy regional rates also vary by non-FTLD TDP-43 type.