Comparative outcomes of trans-arterial radioembolization in patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease-induced HCC: a retrospective analysis.

PURPOSE: Tumorigenesis in NAFLD/NASH-induced HCC is unique and may affect the effectiveness of trans-arterial radioembolization in this population. The purpose of this study was to retrospectively compare the effectiveness of trans-arterial radioembolization for the treatment of hepatocellular carcinoma (HCC) between patients with non-alcoholic steatohepatitis (NASH)/non-alcoholic fatty liver disease (NAFLD) and non-NASH/NAFLD liver disease. MATERIALS AND METHODS: Consecutive patients with HCC who underwent TARE at a single academic institution were retrospectively reviewed. Outcome measures including overall survival (OS), local progression-free survival (PFS), and hepatic PFS as assessed by modified response evaluation criteria in solid tumors (mRECIST) were recorded. Kaplan-Meier and Cox proportional hazard models were utilized to compare progression-free survival and overall survival. RESULTS: 138 separate HCCs in patients treated with TARE between July 2013 and July 2022 were retrospectively identified. Etiologies of HCC included NASH/NAFLD (30/122, 22%), HCV (52/122, 43%), alcoholic liver disease (25/122, 21%), and combined ALD/HCV (14/122, 11%). NASH/NAFLD patients demonstrated a significantly higher incidence of type 2 diabetes mellitus (p < 0.0001). There was no significant difference in overall survival (p = 0.928), local progression-free survival (p = 0.339), or hepatic progression-free survival between the cohorts (p = 0.946) by log-rank analysis. When NASH/NAFLD patients were compared to all combined non-NASH/NAFLD patients, there was no significant difference in OS (HR 1.1, 95% C.I. 0.32-3.79, p = 0.886), local PFS (HR 1.2, 95% C.I. 0.58-2.44, p = 0.639), or hepatic PFS (HR 1.3, 95% C.I. 0.52-3.16, p = 0.595) by log-rank analysis. CONCLUSION: TARE appears to be an equally effective treatment for NASH/NAFLD-induced HCC when compared to other causes of HCC. Further studies in a larger cohort with additional subgroup analyses are warranted.

Increasing Racial and Ethnic Disparities in Ambient Air Pollution-Attributable Morbidity and Mortality in the United States.

BACKGROUND: Ambient nitrogen dioxide (NO2) and fine particulate matter with aerodynamic diameter ≤2.5µm (PM2.5) threaten public health in the US, and systemic racism has led to modern-day disparities in the distribution and associated health impacts of these pollutants. OBJECTIVES: Many studies on environmental injustices related to ambient air pollution focus only on disparities in pollutant concentrations or provide only an assessment of pollution or health disparities at a snapshot in time. In this study, we compare injustices in NO2- and PM2.5-attributable health burdens, considering NO2-attributable health impacts across the entire US; document changing disparities in these health burdens over time (2010-2019); and evaluate how more stringent air quality standards would reduce disparities in health impacts associated with these pollutants. METHODS: Through a health impact assessment, we quantified census tract-level variations in health outcomes attributable to NO2 and PM2.5 using health impact functions that combine demographic data from the US Census Bureau; two spatially resolved pollutant datasets, which fuse satellite data with physical and statistical models; and epidemiologically derived relative risk estimates and incidence rates from the Global Burden of Disease study. RESULTS: Despite overall decreases in the public health damages associated with NO2 and PM2.5, racial and ethnic relative disparities in NO2-attributable pediatric asthma and PM2.5-attributable premature mortality have widened in the US during the last decade. Racial relative disparities in PM2.5-attributable premature mortality and NO2-attributable pediatric asthma have increased by 16% and 19%, respectively, between 2010 and 2019. Similarly, ethnic relative disparities in PM2.5-attributable premature mortality have increased by 40% and NO2-attributable pediatric asthma by 10%. DISCUSSION: Enacting and attaining more stringent air quality standards for both pollutants could preferentially benefit the most marginalized and minoritized communities by greatly reducing racial and ethnic relative disparities in pollution-attributable health burdens in the US. Our methods provide a semi-observational approach to track changes in disparities in air pollution and associated health burdens across the US. https://doi.org/10.1289/EHP11900.

Commonality and variation in mental representations of music revealed by a cross-cultural comparison of rhythm priors in 15 countries.

Music is present in every known society but varies from place to place. What, if anything, is universal to music cognition? We measured a signature of mental representations of rhythm in 39 participant groups in 15 countries, spanning urban societies and Indigenous populations. Listeners reproduced random 'seed' rhythms; their reproductions were fed back as the stimulus (as in the game of 'telephone'), such that their biases (the prior) could be estimated from the distribution of reproductions. Every tested group showed a sparse prior with peaks at integer-ratio rhythms. However, the importance of different integer ratios varied across groups, often reflecting local musical practices. Our results suggest a common feature of music cognition: discrete rhythm 'categories' at small-integer ratios. These discrete representations plausibly stabilize musical systems in the face of cultural transmission but interact with culture-specific traditions to yield the diversity that is evident when mental representations are probed across many cultures.

Interventional Radiology Locoregional Therapies for Intrahepatic Cholangiocarcinoma.

Surgical resection remains the cornerstone of curative treatment for intrahepatic cholangiocarcinoma (iCCA), but this option is only available to a small percentage of patients. For patients with unresectable iCCA, systemic therapy with gemcitabine and platinum-based agents represents the mainstay of treatment; however, the armamentarium has grown to include targeted molecular therapies (e.g., FGFR2 inhibitors), use of adjuvant therapy, liver transplantation in select cases, immunotherapy, and locoregional liver-directed therapies. Despite advances, iCCA remains a challenge due to the advanced stage of many patients at diagnosis. Furthermore, given the improving options for systemic therapy and the fact that the majority of iCCA patients succumb to disease progression in the liver, the role of locoregional therapies has increased. This review will focus on the expanding role of interventional radiology and liver-directed therapies in the treatment of iCCA.

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Public Health Benefits From Improved Identification of Severe Air Pollution Events With Geostationary Satellite Data.

Despite improvements in ambient air quality in the US in recent decades, many people still experience unhealthy levels of pollution. At present, national-level alert-day identification relies predominately on surface monitor networks and forecasters. Satellite-based estimates of surface air quality have rapidly advanced and have the capability to inform exposure-reducing actions to protect public health. At present, we lack a robust framework to quantify public health benefits of these advances in applications of satellite-based atmospheric composition data. Here, we assess possible health benefits of using geostationary satellite data, over polar orbiting satellite data, for identifying particulate air quality alert days (24hr PM2.5 > 35 µg m-3) in 2020. We find the more extensive spatiotemporal coverage of geostationary satellite data leads to a 60% increase in identification of person-alerts (alert days × population) in 2020 over polar-orbiting satellite data. We apply pre-existing estimates of PM2.5 exposure reduction by individual behavior modification and find these additional person-alerts may lead to 1,200 (800-1,500) or 54% more averted PM2.5-attributable premature deaths per year, if geostationary, instead of polar orbiting, satellite data alone are used to identify alert days. These health benefits have an associated economic value of 13 (8.8-17) billion dollars ($2019) per year. Our results highlight one of many potential applications of atmospheric composition data from geostationary satellites for improving public health. Identifying these applications has important implications for guiding use of current satellite data and planning future geostationary satellite missions.

Incidence, risk factors, and complications of acromial stress fractures after reverse total shoulder arthroplasty.

BACKGROUND: An acromial stress fracture (ASF) is an uncommon complication after reverse total shoulder arthroplasty (RTSA) that can have severe clinical consequences on shoulder function. Although patient-specific factors have been identified to influence the risk of ASF, it is unclear whether modifying these factors can minimize risk. Moreover, there is limited information on the treatment outcomes of these fractures. Therefore, the purpose of this study was to determine modifiable risk factors for ASFs and the complication and revision rates of conservatively and operatively managed ASFs. METHODS: The PearlDiver database was queried to identify a cohort of patients who underwent RTSA with minimum 2-year follow-up. Current Procedural Terminology and International Classification of Diseases codes were used to compare the demographic characteristics, comorbidities, and medication use of patients with and without ASFs. Surgical complication and revision rates were compared between operatively and conservatively treated fractures. RESULTS: The overall incidence of ASFs was 1.4%. Patient-specific factors that were independently associated with the occurrence of an ASF included osteoporosis, rheumatologic disease, shoulder corticosteroid injection within 3 months before surgery, and chronic oral corticosteroid use. Among patients with osteoporosis, the initiation of physical therapy within 6 weeks after surgery also increased the risk of ASF. Patients who underwent surgical treatment of ASFs had a revision arthroplasty rate of 7.0% compared to a rate of 3.2% among those with conservatively managed fractures. CONCLUSION: ASFs are infrequent complications that can occur after RTSA. Preoperative factors that affect the quality of bone independently increase the fracture risk. Moreover, this risk can be minimized by avoiding shoulder corticosteroid injections 3 months before surgery and delaying physical therapy exercises among patients with osteoporosis. Surgical fixation of these fractures should be reserved for instances when conservative management has failed given high rates of infection, instability, and revision shoulder arthroplasty.

Ethnoracial Disparities in Nitrogen Dioxide Pollution in the United States: Comparing Data Sets from Satellites, Models, and Monitors.

In the United States (U.S.), studies on nitrogen dioxide (NO2) trends and pollution-attributable health effects have historically used measurements from in situ monitors, which have limited geographical coverage and leave 66% of urban areas unmonitored. Novel tools, including remotely sensed NO2 measurements and estimates of NO2 estimates from land-use regression and photochemical models, can aid in assessing NO2 exposure gradients, leveraging their complete spatial coverage. Using these data sets, we find that Black, Hispanic, Asian, and multiracial populations experience NO2 levels 15-50% higher than the national average in 2019, whereas the non-Hispanic White population is consistently exposed to levels that are 5-15% lower than the national average. By contrast, the in situ monitoring network indicates more moderate ethnoracial NO2 disparities and different rankings of the least- to most-exposed ethnoracial population subgroup. Validating these spatially complete data sets against in situ observations reveals similar performance, indicating that all these data sets can be used to understand spatial variations in NO2. Integrating in situ monitoring, satellite data, statistical models, and photochemical models can provide a semiobservational record, complete geospatial coverage, and increasingly high spatial resolution, enhancing future efforts to characterize, map, and track exposure and inequality for highly spatially heterogeneous pollutants like NO2.

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure activity relationship and the selectivity mechanism.

The mature N-termini of Plasmodium effector proteins confer specificity of export.

IMPORTANCE: Malaria parasites export hundreds of proteins to the cytoplasm of the host red blood cells for their survival. A five amino acid sequence, called the PEXEL motif, is conserved among many exported proteins and is thought to be a signal for export. However, the motif is cleaved inside the endoplasmic reticulum of the parasite, and mature proteins starting from the fourth PEXEL residue travel to the parasite periphery for export. We showed that the PEXEL motif is dispensable for export as long as identical mature proteins can be efficiently produced via alternative means in the ER. We also showed that the exported and non-exported proteins are differentiated at the parasite periphery based on their mature N-termini; however, any discernible export signal within that region remained cryptic. Our study resolves a longstanding paradox in PEXEL protein trafficking.

Unified real-time environmental-epidemiological data for multiscale modeling of the COVID-19 pandemic.

An impressive number of COVID-19 data catalogs exist. However, none are fully optimized for data science applications. Inconsistent naming and data conventions, uneven quality control, and lack of alignment between disease data and potential predictors pose barriers to robust modeling and analysis. To address this gap, we generated a unified dataset that integrates and implements quality checks of the data from numerous leading sources of COVID-19 epidemiological and environmental data. We use a globally consistent hierarchy of administrative units to facilitate analysis within and across countries. The dataset applies this unified hierarchy to align COVID-19 epidemiological data with a number of other data types relevant to understanding and predicting COVID-19 risk, including hydrometeorological data, air quality, information on COVID-19 control policies, vaccine data, and key demographic characteristics.

Histidine-rich protein II nanoparticle delivery of heme iron load drives endothelial inflammation in cerebral malaria.

Histidine-rich protein II (HRPII) is secreted by Plasmodium falciparum during the blood stage of malaria infection. High plasma levels of HRPII are associated with cerebral malaria, a severe and highly fatal complication of malaria. HRPII has been shown to induce vascular leakage, the hallmark of cerebral malaria, in blood-brain barrier (BBB) and animal models. We have discovered an important mechanism for BBB disruption that is driven by unique features of HRPII. By characterizing serum from infected patients and HRPII produced by P. falciparum parasites in culture, we found that HRPII exists in large multimeric particles of 14 polypeptides that are richly laden with up to 700 hemes per particle. Heme loading of HRPII is required for efficient binding and internalization via caveolin-mediated endocytosis in hCMEC/D3 cerebral microvascular endothelial cells. Upon acidification of endolysosomes, two-thirds of the hemes are released from acid-labile binding sites and metabolized by heme oxygenase 1, generating ferric iron and reactive oxygen species. Subsequent activation of the NLRP3 inflammasome and IL-1ß secretion resulted in endothelial leakage. Inhibition of these pathways with heme sequestration, iron chelation, or anti-inflammatory drugs protected the integrity of the BBB culture model from HRPII:heme. Increased cerebral vascular permeability was seen after injection of young mice with heme-loaded HRPII (HRPII:heme) but not with heme-depleted HRPII. We propose that during severe malaria infection, HRPII:heme nanoparticles in the bloodstream deliver an overwhelming iron load to endothelial cells to cause vascular inflammation and edema. Disrupting this process is an opportunity for targeted adjunctive therapies to reduce the morbidity and mortality of cerebral malaria.

Intimately tracking NO2 pollution over the New York City - Long Island Sound land-water continuum: An integration of shipboard, airborne, satellite observations, and models.

Nitrogen dioxide (NO2) pollution remains a serious global problem, particularly near highly populated urbanized coasts that face increasing challenges with climate change. Yet, the combined impact of urban emissions, pollution transport, and complex meteorology on the spatiotemporal dynamics of NO2 along heterogeneous urban coastlines remains poorly characterized. Here, we integrated measurements from different platforms - boats, ground-based networks, aircraft, and satellites - to characterize total column NO2 (TCNO2) dynamics across the land-water continuum in the New York metropolitan area, the most populous area in the United States that often experiences the highest national NO2 levels. Measurements were conducted during the 2018 Long Island Sound Tropospheric Ozone Study (LISTOS), with a main goal to extend surface measurements beyond the coastline - where ground-based air-quality monitoring networks abruptly stop - and over the aquatic environment where peaks in air pollution often occur. Satellite TCNO2 from TROPOMI correlated strongly with Pandora surface measurements (r = 0.87, N = 100) both over land and water. Yet, TROPOMI overall underestimated TCNO2 (MPD = -12%) and missed peaks in NO2 pollution caused by rush hour emissions or pollution accumulation during sea breezes. Aircraft retrievals were in excellent agreement with Pandora (r = 0.95, MPD = -0.3%, N = 108). Stronger agreement was found between TROPOMI, aircraft, and Pandora over land, while over water satellite, and to a lesser extent aircraft, retrievals underestimated TCNO2 particularly in the highly dynamic New York Harbor environment. Combined with model simulations, our shipborne measurements uniquely captured rapid transitions and fine-scale features in NO2 behavior across the New York City - Long Island Sound land-water continuum, driven by the complex interplay of human activity, chemistry, and local scale meteorology. These novel datasets provide critical information for improving satellite retrievals, enhancing air quality models, and informing management decisions, with important implications for the health of diverse communities and vulnerable ecosystems along this complex urban coastline.

Single Portal Segmental Labral Reconstruction of the Hip.

Many techniques have been described for reconstruction of the acetabular labrum, but the procedure is known to be technically rigorous leading to lengthy procedure times and traction times. Increasing efficiency of the procedure with respect to graft preparation and delivery remain areas for potential improvement. We describe a simplified procedure for arthroscopic segmental labral reconstruction using peroneus longus allograft and a single working portal to shuttle the graft into the joint via suture anchors placed at the terminal extents of the graft defect. This method allows for efficient preparation, placement and fixation of the graft that can be completed in under 15 minutes.

An impedance based microfluidic sensor for evaluation of individual red blood cell solute permeability.

-In this paper, we investigate a microfluidic based sensing device for cell membrane permeability measurements in real time with applications in rapid assessment of red blood cell (RBC) quality at the individual cell level. The microfluidic chip was designed with unique abilities to line up the RBCs in the centerline of the microchannel using positive dielectrophoresis (p-DEP) forces, rapid mixing of RBCs with various media (e.g. containing permeating or nonpermeating solutes) injected from different inlets to achieve high mixing efficiency. The chip detects the impedance values of the RBCs within 0.19 s from the start of mixing with other media, at ten electrodes along the length of the channel and enables time series measurements of volume change of individual cell caused by cell osmosis in anisosmotic fluids over a 0.8 s postmixing timespan. This technique enables estimating water permeability of individual cell accurately. Here we first present confirmation of a linear voltage-diameter relationship in polystyrene bead standards. Next, we show that under equilibrium conditions, the voltage-volume relationship in rat red blood cells (RBCs) is linear, corresponding to previously published Boyle van 't Hoff plots. Using rat cells as a model for human, we present the first measurement of water permeability in individual red blood cells and confirm that these data align with previously published population level values for human RBC. Finally, we present preliminary evidence for possible application of our device to identify individual RBCs infected with Plasmodium falciparum malaria parasites. Future developments using this device will address the use of whole blood with non-homogenous cell populations, a task currently performed by clinical Coulter counters.

Postless Tape Augmentation for Posterior Cruciate Ligament Reconstruction.

Many techniques have been described for posterior cruciate ligament (PCL) reconstruction, but residual laxity remains an ongoing challenge. Suture or tape augmentation during ligament reconstruction has become a popular option to prevent graft elongation but comes at the expense of additional costs due to implants for augment fixation, and concern for stress shielding of the graft if the augment and graft are not equally tensioned. We introduce a technique for postless tape augmentation during allograft PCL reconstruction that allows for equal tensioning of graft and augment through the use of a sheath and screw construct without the need for additional implants for augment fixation.

Activation of the Plasmodium Egress Effector Subtilisin-Like Protease 1 Is Mediated by Plasmepsin X Destruction of the Prodomain.

Following each round of replication, daughter merozoites of the malaria parasite Plasmodium falciparum escape (egress) from the infected host red blood cell (RBC) by rupturing the parasitophorous vacuole membrane (PVM) and the RBC membrane (RBCM). A proteolytic cascade orchestrated by a parasite serine protease, subtilisin-like protease 1 (SUB1), regulates the membrane breakdown. SUB1 activation involves primary autoprocessing of the 82-kDa zymogen to a 54-kDa (p54) intermediate that remains bound to its inhibitory propiece (p31) postcleavage. A second processing step converts p54 to the terminal 47-kDa (p47) form of SUB1. Although the aspartic protease plasmepsin X (PM X) has been implicated in the activation of SUB1, the mechanism remains unknown. Here, we show that upon knockdown of PM X, the inhibitory p31-p54 complex of SUB1 accumulates in the parasites. Using recombinant PM X and SUB1, we show that PM X can directly cleave both p31 and p54. We have mapped the cleavage sites on recombinant p31. Furthermore, we demonstrate that the conversion of p54 to p47 can be effected by cleavage at either SUB1 or PM X cleavage sites that are adjacent to one another. Importantly, once the p31 is removed, p54 is fully functional inside the parasites, suggesting that the conversion to p47 is dispensable for SUB1 activity. Relief of propiece inhibition via a heterologous protease is a novel mechanism for subtilisin activation. IMPORTANCE Malaria parasites replicate inside a parasitophorous vacuole within the host red blood cells. The exit of mature progeny from the infected host cells is essential for further dissemination. Parasite exit is a highly regulated, explosive process that involves membrane breakdown. To do this, the parasite utilizes a serine protease called SUB1 that proteolytically activates various effector proteins. SUB1 activity is dependent on an upstream protease called PM X, although the mechanism was unknown. Here, we describe the molecular basis for PM X-mediated SUB1 activation. PM X proteolytically degrades the inhibitory segment of SUB1, thereby activating it. The involvement of a heterologous protease is a novel mechanism for subtilisin activation.

The Perils of Medicalization for Population Health and Health Equity.

Policy Points Medicalization is a historical process by which personal, behavioral, and social issues are increasingly viewed through a biomedical lens and "diagnosed and treated" as individual pathologies and problems by medical authorities. Medicalization in the United States has led to a conflation of "health" and "health care" and a confusion between individual social needs versus the social, political, and economic determinants of health. The essential and important work of population health science, public health practice, and health policy writ large is being thwarted by a medicalized view of health and an overemphasis on personal health services and the health care delivery system as the major focal point for addressing societal health issues and health inequality. Increased recognition of the negative consequences of a medicalized view of health is essential, with a focus on education and training of clinicians and health care managers, journalists, and policymakers.

Role of the Interventional Radiologist in the Treatment of Desmoid Tumors.

Desmoid tumors are locally aggressive soft tissue tumors with variable clinical presentation. As is the case with most relatively rare tumors, a multidisciplinary team approach is required to best manage these patients. Surgical resection, systemic therapy, and radiation therapy have classically been mainstays of treatment for desmoid tumors; however, a more conservative "wait-and-see" approach has been adopted given their high recurrence rates and significant morbidity associated with the aforementioned therapies. Given the challenges of classical treatment methods, interventional radiologists have begun to play a significant role in minimally invasive interventions for desmoid tumors. Herein, the authors review imaging characteristics of desmoid tumors, current management recommendations, and minimally invasive therapeutic intervention options.