Impact of Race and Social Determinants of Health on Outcomes in Patients with Aggressive B-cell nHL Treated with CAR-T.

Healthcare disparities driven by multiple social, economic, and/or environmental factors lead to inequalities in health outcomes. CAR-T cell immunotherapy is an effective therapy for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). However, data are limited on the impact of the convergence of race and social determinants of health on outcomes for patients treated with CAR-T therapy. We examined the impact of interactions between race and insurance type on health care utilization and outcomes in patients treated with CAR-T for aggressive B-NHL. Adult patients with r/r B-NHL treated with CD19 CAR-T were identified between 2015 and 2021 across 13 US academic centers. Insurance type, demographic and clinical data were collected and analyzed via Chi-squared and Kaplan-Meier analysis. Cox multivariable regression (MVA) was used to determine the impact of race/ethnicity and other variables on survival. 466 adult patients were included in our analysis. Median follow-up after CAR-T was 12.7 months. Median progression free survival (mPFS) was longer for Caucasians (11.5 months) than for African Americans (3.5 months, HR 1.56 [1.03-2.4], p=0.04) or Asians (2.7 months, HR 1.7 [1.02-2.67], p=0.04). Differences in median overall survival (mOS) were not significant. For Medicare (n=206) vs Medicaid (n=33) vs private insurance (n=219) vs self-pay (n=7): mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 months (p<0.001) and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 months (p<0.001), respectively. Collectively, our multi-center retrospective analysis showed that race and insurance status can impact outcomes for patients treated with CAR-T cell therapy.

Urban ozone variability using automated machine learning: inference from different feature importance schemes.

Tropospheric ozone is an air pollutant at the ground level and a greenhouse gas which significantly contributes to the global warming. Strong anthropogenic emissions in and around urban environments enhance surface ozone pollution impacting the human health and vegetation adversely. However, observations are often scarce and the factors driving ozone variability remain uncertain in the developing regions of the world. In this regard, here, we conducted machine learning (ML) simulations of ozone variability and comprehensively examined the governing factors over a major urban environment (Ahmedabad) in western India. Ozone precursors (NO2, NO, CO, C5H8 and CH2O) from the CAMS (Copernicus Atmosphere Monitoring Service) reanalysis and meteorological parameters from the ERA5 (European Centre for Medium-Range Weather Forecast's (ECMWF) fifth-generation reanalysis) were included as features in the ML models. Automated ML (AutoML) fitted the deep learning model optimally and simulated the daily ozone with root mean square error (RMSE) of ~2 ppbv reproducing 84-88% of variability. The model performance achieved here is comparable to widely used ML models (RF-Random Forest and XGBoost-eXtreme Gradient Boosting). Explainability of the models is discussed through different schemes of feature importance, including SAGE (Shapley Additive Global importancE) and permutation importance. The leading features are found to be different from different feature importance schemes. We show that urban ozone could be simulated well (RMSE = 2.5 ppbv and R2 = 0.78) by considering first four leading features, from different schemes, which are consistent with ozone photochemistry. Our study underscores the need to conduct science-informed analysis of feature importance from multiple schemes to infer the roles of input variables in ozone variability. AutoML-based studies, exploiting potentials of long-term observations, can strongly complement the conventional chemistry-transport modelling and can also help in accurate simulation and forecast of urban ozone.

Histologic and Immunohistochemical Characterization of GA-Like Pathology in the Rat Subretinal Sodium Iodate Model.

Purpose: Geographic atrophy (GA) is an advanced form of dry age-related macular degeneration with multifactorial etiology and no well-established treatment. A model recapitulating the hallmarks would serve as a key to understanding the underlying pathologic mechanisms better. In this report, we further characterized our previously reported subretinal sodium iodate model of GA. Methods: Retinal degeneration was induced in rats (6-8 weeks old) by subretinal injections of NaIO3 as described previously. Animals were sacrificed at 3, 8 and 12 weeks after injection and eyes were fixed or cryopreserved. Some choroids were processed as flatmounts while other eyes were cryopreserved, sectioned, and immunolabeled with a panel of antibodies. Finally, some eyes were prepared for transmission electron microscopic (TEM) analysis. Results: NaIO3 subretinal injection resulted in a well-defined focal area of retinal pigment epithelium (RPE) degeneration surrounded by viable RPE. These atrophic lesions expanded over time. RPE morphologic changes at the border consisted of hypertrophy, multilayering, and the possible development of a migrating phenotype. Immunostaining of retinal sections demonstrated external limiting membrane descent, outer retinal tubulation (ORT), and extension of Müller cells toward RPE forming a glial membrane in the subretinal space of the atrophic area. TEM findings demonstrated RPE autophagy, cellular constituents of ORT, glial membranes, basal laminar deposits, and defects in Bruch's membrane. Conclusions: In this study, we showed pathologic features of a rodent model resembling human GA in a temporal order through histology, immunofluorescence, and TEM analysis and gained insights into the cellular and subcellular levels of the GA-like phenotypes. Translational Relevance: Despite its acute nature, the expansion of atrophy and the GA-like border in this rat model makes it ideal for studying disease progression and provides a treatment window to test potential therapeutics for GA.

Visualization of choroidal vasculature in pigmented mouse eyes from experimental models of AMD.

A variety of techniques exist to investigate retinal and choroidal vascular changes in experimental mouse models of human ocular diseases. While all have specific advantages, a method for evaluating the choroidal vasculature in pigmented mouse eyes has been more challenging especially for whole mount visualization and morphometric analysis. Here we report a simple, reliable technique involving bleaching pigment prior to immunostaining the vasculature in whole mounts of pigmented mouse choroids. Eyes from healthy adult pigmented C57BL/6J mice were used to establish the methodology. The retina and anterior segment were separated from the choroid. The choroid with retinal pigment epithelial cells (RPE) and sclera was soaked in 1% ethylenediaminetetraacetic acid (EDTA) to remove the RPE. Tissues were fixed in 2% paraformaldehyde (PFA) in phosphate-buffered saline (PBS). Choroids were subjected to melanin bleaching with 10% hydrogen peroxide (H2O2) at 55 °C for 90 min, washed in PBS and then immunostained with anti-podocalyxin antibody to label vascular endothelium followed by Cy3-AffiniPure donkey anti-goat IgG at 4 °C overnight. Images of immunostained bleached choroids were captured using a Zeiss 710 confocal microscope. In addition to control eyes, this method was used to analyze the choroids from subretinal sodium iodate (NaIO3) RPE atrophy and laser-induced choroidal neovascularization (CNV) mouse models. The H2O2 pretreatment effectively bleached the melanin, resulting in a transparent choroid. Immunolabeling with podocalyxin antibody following bleaching provided excellent visualization of choroidal vasculature in the flat perspective. In control choroids, the choriocapillaris (CC) displayed different anatomical patterns in peripapillary (PP), mid peripheral (MP) and far peripheral (FP) choroid. Morphometric analysis of the vascular area (VA) revealed that the CC was most dense in the PP region (87.4 ± 4.3% VA) and least dense in FP (79.9 ± 6.7% VA). CC diameters also varied depending on location from 11.4 ± 1.97 mm in PP to 15.1 ± 3.15 mm in FP. In the NaIO3-injected eyes, CC density was significantly reduced in the RPE atrophic regions (50.7 ± 5.8% VA in PP and 45.8 ± 6.17% VA in MP) compared to the far peripheral non-atrophic regions (82.8 ± 3.8% VA). CC diameters were significantly reduced in atrophic regions (6.35 ± 1.02 mm in PP and 6.5 ± 1.2 mm in MP) compared to non-atrophic regions (14.16 ± 2.12 mm). In the laser-induced CNV model, CNV area was 0.26 ± 0.09 mm2 and luminal diameters of CNV vessels were 4.7 ± 0.9 mm. Immunostaining on bleached choroids with anti-podocalyxin antibody provides a simple and reliable tool for visualizing normal and pathologic choroidal vasculature in pigmented mouse eyes for quantitative morphometric analysis. This method will be beneficial for examining and evaluating the effects of various treatment modalities on the choroidal vasculature in mouse models of ocular diseases such as age-related macular degeneration, and degenerative genetic diseases.

Pathologic vs. protective roles of hypoxia-inducible factor 1 in RPE and photoreceptors in wet vs. dry age-related macular degeneration.

It has previously been reported that antioxidant vitamins can help reduce the risk of vision loss associated with progression to advanced age-related macular degeneration (AMD), a leading cause of visual impairment among the elderly. Nonetheless, how oxidative stress contributes to the development of choroidal neovascularization (CNV) in some AMD patients and geographic atrophy (GA) in others is poorly understood. Here, we provide evidence demonstrating that oxidative stress cooperates with hypoxia to synergistically stimulate the accumulation of hypoxia-inducible factor (HIF)-1α in the retinal pigment epithelium (RPE), resulting in increased expression of the HIF-1-dependent angiogenic mediators that promote CNV. HIF-1 inhibition blocked the expression of these angiogenic mediators and prevented CNV development in an animal model of ocular oxidative stress, demonstrating the pathological role of HIF-1 in response to oxidative stress stimulation in neovascular AMD. While human-induced pluripotent stem cell (hiPSC)-derived RPE monolayers exposed to chemical oxidants resulted in disorganization and disruption of their normal architecture, RPE cells proved remarkably resistant to oxidative stress. Conversely, equivalent doses of chemical oxidants resulted in apoptosis of hiPSC-derived retinal photoreceptors. Pharmacologic inhibition of HIF-1 in the mouse retina enhanced-while HIF-1 augmentation reduced-photoreceptor apoptosis in two mouse models for oxidative stress, consistent with a protective role for HIF-1 in photoreceptors in patients with advanced dry AMD. Collectively, these results suggest that in patients with AMD, increased expression of HIF-1α in RPE exposed to oxidative stress promotes the development of CNV, but inadequate HIF-1α expression in photoreceptors contributes to the development of GA.

Reconstructing the feeding ecology of Cambrian sponge reefs: the case for active suspension feeding in Archaeocyatha.

Sponge-grade Archaeocyatha were early Cambrian biomineralizing metazoans that constructed reefs globally. Despite decades of research, many facets of archaeocyath palaeobiology remain unclear, making it difficult to reconstruct the palaeoecology of Cambrian reef ecosystems. Of specific interest is how these organisms fed; previous experimental studies have suggested that archaeocyaths functioned as passive suspension feeders relying on ambient currents to transport nutrient-rich water into their central cavities. Here, we test this hypothesis using computational fluid dynamics (CFD) simulations of digital models of select archaeocyath species. Our results demonstrate that, given a range of plausible current velocities, there was very little fluid circulation through the skeleton, suggesting obligate passive suspension feeding was unlikely. Comparing our simulation data with exhalent velocities collected from extant sponges, we infer an active suspension feeding lifestyle for archaeocyaths. The combination of active suspension feeding and biomineralization in Archaeocyatha may have facilitated the creation of modern metazoan reef ecosystems.

Outcomes of patients with secondary central nervous system lymphoma following CAR T-cell therapy: a multicenter cohort study.

Chimeric antigen receptor T-cell therapy (CAR-T) has been successful in treating relapsed/refractory B-cell lymphomas. However, its role in the treatment of diseases involving the central nervous system (CNS) is not well studied. We performed a multicenter retrospective cohort study to evaluate the outcomes of patients with secondary CNS lymphoma (SCNSL) who received CAR-T. Eligibility required active CNSL at the time of apheresis. The objectives included evaluation of overall survival (OS), progression-free survival (PFS), identification of predictors of complete response (CR) post-CAR-T, and assessment of risk factors for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Sixty-one patients were included in the analysis. The overall response rate was 68% with a CR rate of 57%. In the multivariable analysis, patients who experienced any grade CRS had higher odds of achieving CR (OR = 3.9, 95% CI = 1.01-15.39, p = 0.047). The median PFS was 3.3 months (95% CI = 2.6-6.0 months) with 6- and 12-month PFS rates of 35% and 16%, respectively. The median OS was 7.6 months (95% CI = 5.0-13.5 months) with 6- and 12-month OS rates of 59% and 41%, respectively. Any grade CRS and ICANS were 70% (n = 43) and 57% (n = 34), respectively with grade ≥ 3 CRS and ICANS rates of 16% and 44%. Factors associated with increased risk of CRS and ICANS included receiving axi-cel or having leptomeningeal ± parenchymal + CNS involvement, respectively. Despite achieving high response rates, most patients experience early relapse or death following CAR-T in SCNSL. The current study provides a benchmark for future trials exploring novel therapeutic options in SCNSL.

Clinical Characteristics of Hospitalized Patients With COVID-19: A Retrospective Cohort Study in Pakistan.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of severe upper respiratory tract infections known as COVID-19. This single-center study aimed to investigate the demographics, comorbidities, symptoms, and disease severity of COVID-19 patients in Pakistan. METHODS: A retrospective descriptive study was conducted at the Pakistan Kidney and Liver Institute and Research Center from April 2020 to August 2020. A total of 430 PCR-positive COVID-19 patients were categorized into symptomatic and asymptomatic groups. The symptomatic group was further classified into severe and non-severe subgroups. Patients' demographics, comorbid conditions, presenting symptoms, laboratory parameters, and clinical outcomes were assessed in these two subgroups. Statistical tests were applied to determine significant differences. RESULTS: A total of 430 patients with COVID-19 presented in our center, of whom 334 (78%) were symptomatic and included in the study. Severe disease was observed in 83 (24.8%) symptomatic patients, with a male predominance (75.9%) and higher mean age (61.7 ± 13.2). Travel to high-risk destinations (p < 0.002) and close contact with COVID-19 patients (p < 0.001) were significant risk factors. Major comorbid conditions included diabetes mellitus (30.5%) and hypertension (39.8%). Frequent symptoms included fever (71.8%), cough (68.8%), dyspnea (53.8%), and myalgias (35.9%). Higher C-reactive protein (median = 12.76 vs. 1.45, p = 0.001), ferritin (median = 996.70 vs. 628, p = 0.004), and D-dimers (median = 1121 vs. 439.50, p = 0.009) were noted in severe vs non-severe disease. Lymphopenia was more prevalent in severe vs. non-severe disease (83.1% vs. 14.3% p-value = 0.033). More deaths (28.9%) and ICU admissions (53%) with a prolonged hospital stay (median = 25 days, IQR = 16.0-31.0) were noted in the severe group. CONCLUSION: This retrospective study provides insights into the clinical characteristics and outcomes of COVID-19 patients. Age, male gender, comorbidities, and specific symptoms were associated with disease severity. Inflammatory markers, including D-dimers, ferritin, and CRP, were elevated in severe cases. These findings contribute to a better understanding of COVID-19 and may aid in clinical management and decision-making for patients affected by the disease.

Validation of automated data abstraction for SCCM discovery VIRUS COVID-19 registry: practical EHR export pathways (VIRUS-PEEP).

Background: The gold standard for gathering data from electronic health records (EHR) has been manual data extraction; however, this requires vast resources and personnel. Automation of this process reduces resource burdens and expands research opportunities. Objective: This study aimed to determine the feasibility and reliability of automated data extraction in a large registry of adult COVID-19 patients. Materials and methods: This observational study included data from sites participating in the SCCM Discovery VIRUS COVID-19 registry. Important demographic, comorbidity, and outcome variables were chosen for manual and automated extraction for the feasibility dataset. We quantified the degree of agreement with Cohen's kappa statistics for categorical variables. The sensitivity and specificity were also assessed. Correlations for continuous variables were assessed with Pearson's correlation coefficient and Bland-Altman plots. The strength of agreement was defined as almost perfect (0.81-1.00), substantial (0.61-0.80), and moderate (0.41-0.60) based on kappa statistics. Pearson correlations were classified as trivial (0.00-0.30), low (0.30-0.50), moderate (0.50-0.70), high (0.70-0.90), and extremely high (0.90-1.00). Measurements and main results: The cohort included 652 patients from 11 sites. The agreement between manual and automated extraction for categorical variables was almost perfect in 13 (72.2%) variables (Race, Ethnicity, Sex, Coronary Artery Disease, Hypertension, Congestive Heart Failure, Asthma, Diabetes Mellitus, ICU admission rate, IMV rate, HFNC rate, ICU and Hospital Discharge Status), and substantial in five (27.8%) (COPD, CKD, Dyslipidemia/Hyperlipidemia, NIMV, and ECMO rate). The correlations were extremely high in three (42.9%) variables (age, weight, and hospital LOS) and high in four (57.1%) of the continuous variables (Height, Days to ICU admission, ICU LOS, and IMV days). The average sensitivity and specificity for the categorical data were 90.7 and 96.9%. Conclusion and relevance: Our study confirms the feasibility and validity of an automated process to gather data from the EHR.

Network pharmacology and molecular docking study-based approach to explore mechanism of benzimidazole-based anthelmintics for the treatment of lung cancer.

Emerging studies have reported the potential anticancer activity of benzimidazole-based anthelmintics (BBA) against lung cancer (LC). However, mechanism underlying the anticancer activity of BBA is unclear. Therefore, in the current study, network pharmacology and molecular docking-based approach were used to explore the potential molecular mechanism for the treatment of LC. The potential targets for BBA were obtained from multiple databases including SwissTargetPrediction, Drug Bank, Therapeutic Target Database, and Comparative Toxicogenomics Database while LC targets were collected from DisGeNet gene discovery platform, Integrated Genomic Database of NSCLC, Catalogue of Somatic Mutations in Cancer and Online Mendelian Inheritance in Man database. Protein-protein interaction (PPI) diagram of common targets was constructed using STRING online platform. Topological analysis was performed using Cytoscape and gene enrichment analysis was conducted using FunRich software. Highest degree targets were then confirmed using molecular docking and molecular dynamics simulations. The BBA were prioritized according to their S scores, with ricobendazole ranking highest followed by flubendazole, fenbendazole, mebendazole, triclabendazole, albendazole, oxibendazole, parbendazole, thiabendazole and oxfendazole. The potential targets of BBA identified using topological analysis and molecular docking were found to be CCND1 (cyclin D1), EGFR (Epidermal Growth Factor Receptor), ERBB2 (Erb-B2 Receptor Tyrosine Kinase 2/CD340), PTGS2 (Prostaglandin-endoperoxide synthase 2), and SRC (Proto-oncogene tyrosine-protein kinase). Furthermore, molecular dynamics confirmed that CCND1 and EGFR are the potential targets of ricobendazole for the treatment of LC. BBA can be further explored as a therapeutic strategy for the treatment of lung cancer under in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.

Anesthesia Services in Low- and Middle-Income Countries: The Fragile Point for Safe Surgery and Patient Safety.

The Safe Surgery Saves Life campaign of the World Health Organization advocates patient safety best practices during surgical procedures. Anesthesia service is indivisible from the patient safety best practices. Although anesthesia services are safer than ever before, safe delivery of anesthesia service and patient safety depends significantly on the availability of qualified anesthesiologists, the knowledge and competency of anesthesiologists, the work environment, and the availability of essential equipment and monitoring facilities. Despite anesthesiologists being the midstream of perioperative care, their role and service are often underacknowledged, especially in low- and middle-income countries (LMICs). Anesthesia services in LMICs face myriad challenges such as a shortage of skilled personnel, inadequate resources, limited training opportunities, and minimal administrative say, which act as the fragile point in the chain of safe surgery delivery. Specific solutions should focus on strengthening the anesthesia workforce, providing fair remuneration and incentives, advocating for anesthesia autonomy, and facilitating access to educational resources. Nevertheless, managing these problems requires a collaborative effort involving governments, healthcare organizations, and international stakeholders to develop sustainable solutions and prioritize the well-being of both anesthesia providers and patients. This editorial focuses on it briefly, emphasizing the anesthesia of rural healthcare service and patient safety.

Multicomponent Domino Reaction for Concise Access to 2-Amino-Substituted 1,3,4 Oxadiazoles via Smiles Rearrangement.

A multicomponent domino reaction has been developed for the preparation of N-substituted 2-amino-1,3,4-oxadiazoles directly from various hydrazides (32 examples). The formation of 2-amino-1,3,4-oxadiazole involves the Smiles rearrangement of thiazolidinone, which results in the formation of carbodiimide intermediate that concomitantly undergoes amide-imidic acid tautomerism followed by cyclization. The protocol developed has wide applicability and provides the desired 2-amino-1,3,4-oxadiazole in excellent yields. The GSD studies of NMR spectra of aliphatic substrates (4di, 4dh) revealed the formation of three products, whereas, in the case of allylic and benzylic substrates, thiazolidinones were obtained as the sole products. Furthermore, to elucidate the plausible mechanism, DFT studies were performed affirming carbodiimide as the crucial intermediate for the interconversion of thiazolidinone to oxadiazole.

Raptorial appendages of the Cambrian apex predator Anomalocaris canadensis are built for soft prey and speed.

The stem-group euarthropod Anomalocaris canadensis is one of the largest Cambrian animals and is often considered the quintessential apex predator of its time. This radiodont is commonly interpreted as a demersal hunter, responsible for inflicting injuries seen in benthic trilobites. However, controversy surrounds the ability of A. canadensis to use its spinose frontal appendages to masticate or even manipulate biomineralized prey. Here, we apply a new integrative computational approach, combining three-dimensional digital modelling, kinematics, finite-element analysis (FEA) and computational fluid dynamics (CFD) to rigorously analyse an A. canadensis feeding appendage and test its morphofunctional limits. These models corroborate a raptorial function, but expose inconsistencies with a capacity for durophagy. In particular, FEA results show that certain parts of the appendage would have experienced high degrees of plastic deformation, especially at the endites, the points of impact with prey. The CFD results demonstrate that outstretched appendages produced low drag and hence represented the optimal orientation for speed, permitting acceleration bursts to capture prey. These data, when combined with evidence regarding the functional morphology of its oral cone, eyes, body flaps and tail fan, suggest that A. canadensis was an agile nektonic predator that fed on soft-bodied animals swimming in a well-lit water column above the benthos. The lifestyle of A. canadensis and that of other radiodonts, including plausible durophages, suggests that niche partitioning across this clade influenced the dynamics of Cambrian food webs, impacting on a diverse array of organisms at different sizes, tiers and trophic levels.

Costs and Consequences of a Novel Emergency Department Sepsis Diagnostic Test: The IntelliSep Index.

Sepsis causes 270,000 deaths and costs $38 billion annually in the United States. Most cases of sepsis present in the emergency department (ED), where rapid diagnosis remains challenging. The IntelliSep Index (ISI) is a novel diagnostic test that analyzes characteristics of WBC structure and provides a reliable early signal for sepsis. This study performs a cost-consequence analysis of the ISI relative to procalcitonin for early sepsis diagnosis in the ED. PERSPECTIVE: U.S. healthcare system. SETTING: Community hospital ED. METHODS: A decision tree analysis was performed comparing ISI with procalcitonin. Model parameters included prevalence of sepsis, sensitivity and specificity of diagnostic tests (both ISI and procalcitonin), costs of hospitalization, and mortality rate stratified by diagnostic test result. Mortality and prevalence of sepsis were estimated from best available literature. Costs were estimated based on an analysis of a large, national discharge dataset, and adjusted to 2018 U.S. dollars. Outcomes included expected costs and survival. RESULTS: Assuming a confirmed sepsis prevalence of 16.9% (adjudicated to Sepsis-3), the ISI strategy had an expected cost per patient of $3,849 and expected survival rate of 95.08%, whereas the procalcitonin strategy had an expected cost of $4,656 per patient and an expected survival of 94.98%. ISI was both less costly and more effective than procalcitonin, primarily because of fewer false-negative results. These results were robust in sensitivity analyses. CONCLUSIONS: ISI was both less costly and more effective in preventing mortality than procalcitonin, primarily because of fewer false-negative results. The ISI may provide health systems with a higher-value diagnostic test in ED sepsis evaluation. Additional work is needed to validate these results in clinical practice.

A new species of Nanhsiungchelys (Testudines: Cryptodira: Nanhsiungchelyidae) from the Upper Cretaceous of Nanxiong Basin, China.

Nanhsiungchelyidae are a group of large turtles that lived in Asia and North America during the Cretaceous. Here we report a new species of nanhsiungchelyid, Nanhsiungchelys yangi sp. nov., from the Upper Cretaceous of Nanxiong Basin, China. The specimen consists of a well-preserved skull and lower jaw, as well as the anterior parts of the carapace and plastron. The diagnostic features of Nanhsiungchelys include a large entire carapace length (∼55.5 cm), a network of sculptures consisting of pits and ridges on the surface of the skull and shell, shallow cheek emargination and temporal emargination, deep nuchal emargination, and a pair of anterolateral processes on the carapace. However, Nanhsiungchelys yangi differs from the other species of Nanhsiungchelys mainly in having a triangular-shaped snout (in dorsal view) and wide anterolateral processes on the carapace. Additionally, some other characteristics (e.g., the premaxilla is higher than wide, the maxilla is unseen in dorsal views, a small portion of the maxilla extends posterior and ventral of the orbit, and the parietal is bigger than the frontal) are strong evidence to distinguish Nanhsiungchelys yangi from Nanhsiungchelys wuchingensis. A phylogenetic analysis of nanhsiungchelyids places Nanhsiungchelys yangi and Nanhsiungchelys wuchingensis as sister taxa. Nanhsiungchelys yangi and some other nanhsiungchelyids bear distinct anterolateral processes on the carapace, which have not been reported in any extant turtles and may have played a role in protecting the head. The Nanxiong Basin was extremely hot during the Late Cretaceous, and so we suggest that nanhsiungchelyids might have immersed themselves in mud or water to avoid the heat, similar to some extant tortoises. If they were capable of swimming, our computer simulations of fluid flow suggest the anterolateral processes could have reduced drag during locomotion.

Cambrian stem-group ambulacrarians and the nature of the ancestral deuterostome.

Deuterostomes are characterized by some of the most widely divergent body plans in the animal kingdom. These striking morphological differences have hindered efforts to predict ancestral characters, with the origin and earliest evolution of the group remaining ambiguous. Several iconic Cambrian fossils have been suggested to be early deuterostomes and hence could help elucidate ancestral character states. However, their phylogenetic relationships are controversial. Here, we describe new, exceptionally preserved specimens of the discoidal metazoan Rotadiscus grandis from the early Cambrian Chengjiang biota of China. These reveal a previously unknown double spiral structure, which we interpret as a chordate-like covering to a coelomopore, located adjacent to a horseshoe-shaped tentacle complex. The tentacles differ in key aspects from those seen in lophophorates and are instead more similar to the tentacular systems of extant pterobranchs and echinoderms. Thus, Rotadiscus exhibits a chimeric combination of ambulacrarian and chordate characters. Phylogenetic analyses recover Rotadiscus and closely related fossil taxa as stem ambulacrarians, filling a significant morphological gap in the deuterostome tree of life. These results allow us to reconstruct the ancestral body plans of major clades of deuterostomes, revealing that key traits of extant forms, such as a post-anal region, gill bars, and a U-shaped gut, evolved through convergence.

Efficacy of checkpoint inhibition after CAR-T failure in aggressive B-cell lymphomas: outcomes from 15 US institutions.

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes.

Clinicopathologic Findings in Three Siblings With Geographic Atrophy.

Purpose: Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly worldwide. Clinical imaging and histopathologic studies are crucial to understanding disease pathology. This study combined clinical observations of three brothers with geographic atrophy (GA), followed for 20 years, with histopathologic analysis. Methods: For two of the three brothers, clinical images were taken in 2016, 2 years prior to death. Immunohistochemistry, on both flat-mounts and cross sections, histology, and transmission electron microscopy were used to compare the choroid and retina in GA eyes to those of age-matched controls. Results: Ulex europaeus agglutinin (UEA) lectin staining of the choroid demonstrated a significant reduction in the percent vascular area and vessel diameter. In one donor, histopathologic analysis demonstrated two separate areas with choroidal neovascularization (CNV). Reevaluation of swept-source optical coherence tomography angiography (SS-OCTA) images revealed CNV in two of the brothers. UEA lectin also revealed a significant reduction in retinal vasculature in the atrophic area. A subretinal glial membrane, composed of processes positive for glial fibrillary acidic protein and/or vimentin, occupied areas identical to those of retinal pigment epithelium (RPE) and choroidal atrophy in all three AMD donors. SS-OCTA also demonstrated presumed calcific drusen in the two donors imaged in 2016. Immunohistochemical analysis and alizarin red S staining verified calcium within drusen, which was ensheathed by glial processes. Conclusions: This study demonstrates the importance of clinicohistopathologic correlation studies. It emphasizes the need to better understand how the symbiotic relationship between choriocapillaris and RPE, glial response, and calcified drusen impact GA progression.

Atypical Presentations of Myocardial Infarction: A Systematic Review of Case Reports.

There is a rising incidence of coronary artery diseases and myocardial infarction (MI). Mortality associated with acute MI (AMI) is directly linked to the time to receive treatment and missed diagnoses. Although health professionals are aware of typical AMI presentation, atypical MI is difficult to diagnose, which on the other hand, is likely to have an impact on morbidity and mortality. Therefore, it is prudent to know such atypical presentations, especially for emergency and primary care physicians. We aimed to systematically evaluate the clinical presentations of atypical MI and analyze them to characterize the common clinical presentations of atypical MI. We researched the PubMed database, did citation tracking, and performed Google Scholar advanced search to find the cases reported on the atypical presentation of MI published from January 2000 to September 2022. Articles of all languages were included; Google Translate was used to translate articles published in languages other than English. A total of 496 (56 PubMed articles, 340 citations from included PubMed articles, and 100 articles from Google Scholar advanced search) were screened; 52 case reports were evaluated, and their data were analyzed. Atypical presentations of myocardial infarction are vast; patients may have chest pain without typical characteristics of angina pain or may not have chest pain. No typical characterization could be done. Most patients were in their fifth decade or above of their life and commonly presented with pain and discomfort in the abdomen, head, and neck regions. Prodromal symptoms were consistent findings, and many patients had two to three comorbidities out of four common comorbidities, i.e., diabetes, hypertension, dyslipidemia, and substance abuse. A patient who is 50 years old or more, having comorbidities such as diabetes, hypertension, dyslipidemia, history of tobacco or marijuana usage, presenting with prodromal symptoms like shortness of breath, dizziness, fatigue, syncope, gastrointestinal discomfort or head/neck pain should be suspected for atypical MI.