The West Antarctic Ice Sheet may not be vulnerable to marine ice cliff instability during the 21st century.

The collapse of ice shelves could expose tall ice cliffs at ice sheet margins. The marine ice cliff instability (MICI) is a hypothesis that predicts that, if these cliffs are tall enough, ice may fail structurally leading to self-sustained retreat. To date, projections that include MICI have been performed with a single model based on a simple parameterization. Here, we implement a physically motivated parameterization in three ice sheet models and simulate the response of the Amundsen Sea Embayment after a hypothetical collapse of floating ice. All models show that Thwaites Glacier would not retreat further in the 21st century. In another set of simulations, we force the grounding line to retreat into Thwaites' deeper basin to expose a taller cliff. In these simulations, rapid thinning and velocity increase reduce the calving rate, stabilizing the cliff. These experiments show that Thwaites may be less vulnerable to MICI than previously thought, and model projections that include this process should be re-evaluated.

Air pollution impacts from warehousing in the United States uncovered with satellite data.

Regulators, environmental advocates, and community groups in the United States (U.S.) are concerned about air pollution associated with the proliferating e-commerce and warehousing industries. Nationwide datasets of warehouse locations, traffic, and satellite observations of the traffic-related pollutant nitrogen dioxide (NO2) provide a unique capability to evaluate the air quality and environmental equity impacts of these geographically-dispersed emission sources. Here, we show that the nearly 150,000 warehouses in the U.S. worsen local traffic-related air pollution with an average near-warehouse NO2 enhancement of nearly 20% and are disproportionately located in marginalized and minoritized communities. Near-warehouse truck traffic and NO2 significantly increase as warehouse density and the number of warehouse loading docks and parking spaces increase. Increased satellite-observed NO2 near warehouses underscores the need for indirect source rules, incentives for replacing old trucks, and corporate commitments towards electrification. Future ground-based monitoring campaigns may help track impacts of individual or small clusters of facilities.

Concomitant Medial Collateral Ligament Injury Increases the Risk of Revision Anterior Cruciate Ligament Reconstruction.

PURPOSE: To compare rates of revisions between patients with isolated anterior cruciate ligament (ACL) reconstruction and those who had concomitant medial collateral ligament (MCL) injuries managed either operatively or nonoperatively at the time of index anterior cruciate ligament reconstruction (ACLR). METHODS: Using laterality-specific International Classification of Diseases, Tenth Revision (ICD-10) and Current Procedural Terminology (CPT) codes, we queried the PearlDiver-Mariner Database for all patients who underwent ACLR between 2016 and 2020. Patients were included if they were ages 15 or older and had a minimum of 2 years of follow-up after index ACLR. Patients were then divided into cohorts by presence or absence of concomitant MCL injury. The cohort of concomitant MCL injuries was further subdivided into those with MCL injuries managed nonoperatively, with MCL repair, or with MCL reconstruction at the time of index ACLR. Multivariate regression was performed between cohorts to evaluate for factors associated with revision ACLR. RESULTS: We identified 47,306 patients with isolated ACL injuries and 10,846 with concomitant MCL and ACL injuries. In total, 93% of patients with concomitant MCL injuries had their MCL treated nonoperatively; however, the annual proportion of patients being surgically managed for their MCL injury increased by 70% from 2016 to 2020. Concomitant MCL injury patients had greater odds of undergoing revision ACLR compared with patients with isolated ACL injuries (odds ratio 1.50, 95% confidence interval 1.36-1.66, P < .001). Among patients with concomitant MCL injuries, surgically managed patients had a greater risk of revision ACLR compared with nonoperatively managed MCL injuries (odds ratio 1.39, 95% confidence interval 1.01-1.86, P = .034). CONCLUSIONS: Despite an increase in operatively managed concomitant MCL injuries, most concomitant MCL injuries were still managed nonoperatively at the time of ACLR. Patients with concomitant MCL injuries, particularly those managed operatively, at the time of ACLR are at increased risk of requiring revision ACLR compared with those with isolated ACL injuries. LEVEL OF EVIDENCE: Level III, retrospective comparative case series.

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis.

Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum parasites internalize and digest abundant host hemoglobin within the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) that lacks key active-site residues and has lost canonical HO activity. The cellular role of this unusual protein that underpins its retention by parasites has been unknown. To unravel PfHO function, we first determined a 2.8 Å-resolution X-ray structure that revealed a highly α-helical fold indicative of distant HO homology. Localization studies unveiled PfHO targeting to the apicoplast organelle, where it is imported and undergoes N-terminal processing but retains most of the electropositive transit peptide. We observed that conditional knockdown of PfHO was lethal to parasites, which died from defective apicoplast biogenesis and impaired isoprenoid-precursor synthesis. Complementation and molecular-interaction studies revealed an essential role for the electropositive N-terminus of PfHO, which selectively associates with the apicoplast genome and enzymes involved in nucleic acid metabolism and gene expression. PfHO knockdown resulted in a specific deficiency in levels of apicoplast-encoded RNA but not DNA. These studies reveal an essential function for PfHO in apicoplast maintenance and suggest that Plasmodium repurposed the conserved HO scaffold from its canonical heme-degrading function in the ancestral chloroplast to fulfill a critical adaptive role in organelle gene expression.

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.

The Need for Historical Fluency in Pandemic Law and Policy.

The primary claim of this essay is that historical fluency is required for effective work in crafting legal and policy interventions as a part of public health emergency preparedness and response (PHEPR). At a broad level, public health law is explicitly recognized as a key systems-level component of PHEPR practice.1 This essay therefore focuses on the extent to which historical fluency is necessary or at least useful to all aspects of PHEPR that draw on or deploy legal and policy mechanisms (e.g., design, planning, implementation, dissemination, monitoring and evaluation, etc.). The essay collectively refers to these legal and policy mechanisms as epidemic law and policy response (ELAPR). Part I explains the concept of historical fluency. Part II explores the foundations of public health law both as a way of highlighting key structural features of ELAPR and in supporting the claim that historical fluency is critical for ELAPR. Part III applies the previous arguments to a specific case study to highlight the promise and power of historical fluency - the outbreak of bubonic plague in San Francisco in 1900. Tracking this essay's pragmatic focus, part IV offers several recommendations for how specifically historical fluency in public health law and ethics can be operationalized in PHEPR practice and policy. Part V summarizes and concludes.

Integrating Public Health Ethics into Public Health Policymaking: Being in the Room Where It Happens.

This commentary takes up a challenge posed by Franklin Miller in a 2022 essay in Bioethics Forum. Dr. Miller queried whether bioethicists could be useful in public health policy contexts and while he refrained from issuing an ultimate opinion, did identify several challenges to such utility. The current piece responds to the challenges Dr. Miller identifies and argues that with appropriate training, public health ethicists can be of service in virtually any context in which public health policies are deliberated and decided.

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.

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.

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.

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.

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.