Flow in fetoplacental-like microvessels in vitro enhances perfusion, barrier function, and matrix stability.

Proper placental vascularization is vital for pregnancy outcomes, but assessing it with animal models and human explants has limitations. We introduce a 3D in vitro model of human placenta terminal villi including fetal mesenchyme and vascular endothelium. By coculturing HUVEC, placental fibroblasts, and pericytes in a macrofluidic chip with a flow reservoir, we generate fully perfusable fetal microvessels. Pressure-driven flow facilitates microvessel growth and remodeling, resulting in early formation of interconnected and lasting placental-like vascular networks. Computational fluid dynamics simulations predict shear forces, which increase microtissue stiffness, decrease diffusivity, and enhance barrier function as shear stress rises. Mass spectrometry analysis reveals enhanced protein expression with flow, including matrix stability regulators, proteins associated with actin dynamics, and cytoskeleton organization. Our model provides a powerful tool for deducing complex in vivo parameters, such as shear stress on developing vascularized placental tissue, and holds promise for unraveling gestational disorders related to the vasculature.

Completeness of Race and Ethnicity Reporting in Person-Level COVID-19 Surveillance Data, 50 States, April 2020-December 2021.

OBJECTIVES: Black, Indigenous, and People of Color have borne a disproportionate incidence of COVID-19 cases in the United States. However, few studies have documented the completeness of race and ethnicity reporting in national COVID-19 surveillance data. The objective of this study was to describe the completeness of race and ethnicity ascertainment in person-level data received by the Centers for Disease Control and Prevention (CDC) through national COVID-19 case surveillance. METHODS: We compared COVID-19 cases with "complete" (ie, per Office of Management and Budget 1997 revised criteria) data on race and ethnicity from CDC person-level surveillance data with CDC-reported aggregate counts of COVID-19 from April 5, 2020, through December 1, 2021, in aggregate and by state. RESULTS: National person-level COVID-19 case surveillance data received by CDC during the study period included 18 881 379 COVID-19 cases with complete ascertainment of race and ethnicity, representing 39.4% of all cases reported to CDC in aggregate (N = 47 898 497). Five states (Georgia, Hawaii, Nebraska, New Jersey, and West Virginia) did not report any COVID-19 person-level cases with multiple racial identities to CDC. CONCLUSION: Our findings highlight a high degree of missing data on race and ethnicity in national COVID-19 case surveillance, enhancing our understanding of current challenges in using these data to understand the impact of COVID-19 on Black, Indigenous, and People of Color. Streamlining surveillance processes to decrease reporting incidence and align reporting requirements with an Office of Management and Budget-compliant collection of data on race and ethnicity would improve the completeness of data on race and ethnicity for national COVID-19 case surveillance.

Pericytes and shear stress each alter the shape of a self-assembled vascular network.

Blood vessel morphology is dictated by mechanical and biochemical cues. Flow-induced shear stress and pericytes both play important roles, and they have previously been studied using on-chip vascular networks to uncover their connection to angiogenic sprouting and network stabilization. However, it is unknown which shear stress values promote angiogenesis, how pericytes are directed to sprouts, and how shear stress and pericytes affect the overall vessel morphology. Here, we employed a microfluidic device to study these phenomena in three-dimensional (3D) self-assembled vasculature. Computational fluid dynamics solver (COMSOL) simulations indicated that sprouts form most frequently at locations of relatively low shear stresses (0.5-1.5 dyn cm-2). Experimental results show that pericytes limit vascular diameter. Interestingly, when treated with imatinib or crenolanib, which are chemotherapeutic drugs and inhibitors of platelet-derived growth factor receptor ß (PDGFRß), the pericyte coverage of vessels decreased significantly but vessel diameter remained unchanged. This furthers our understanding of the mechanisms underlying vascular development and demonstrates the value of this microfluidic device in future studies on drug development and vascular biology.

COVID-19 Among Non-Hispanic American Indian and Alaska Native People Residing in Urban Areas Before and After Vaccine Rollout-Selected States and Counties, United States, January 2020-October 2021.

Objectives. To evaluate COVID-19 disparities among non-Hispanic American Indian/Alaska Native (AI/AN) and non-Hispanic White persons in urban areas. Methods. Using COVID-19 case surveillance data, we calculated cumulative incidence rates and risk ratios (RRs) among non-Hispanic AI/AN and non-Hispanic White persons living in select urban counties in the United States by age and sex during January 22, 2020, to October 19, 2021. We separated cases into prevaccine (January 22, 2020-April 4, 2021) and postvaccine (April 5, 2021-October 19, 2021) periods. Results. Overall in urban areas, the COVID-19 age-adjusted rate among non-Hispanic AI/AN persons (n = 47 431) was 1.66 (95% confidence interval [CI] = 1.36, 2.01) times that of non-Hispanic White persons (n = 2 301 911). The COVID-19 prevaccine age-adjusted rate was higher (8227 per 100 000; 95% CI = 6283, 10 770) than was the postvaccine rate (3703 per 100 000; 95% CI = 3235, 4240) among non-Hispanic AI/AN compared with among non-Hispanic White persons (2819 per 100 000; 95% CI = 2527, 3144; RR = 1.31; 95% CI = 1.17, 1.48). Conclusions. This study highlights disparities in COVID-19 between non-Hispanic AI/AN and non-Hispanic White persons in urban areas. These findings suggest that COVID-19 vaccination and other public health efforts among urban AI/AN communities can reduce COVID-19 disparities in urban AI/AN populations. (Am J Public Health. 2022;112(10):1489-1497. https://doi.org/10.2105/AJPH.2022.306966).

Concussion symptoms and temporary accommodations using a student-centered return to learn care plan.

BACKGROUND: Many students return to school after concussion with symptoms but without formal support. OBJECTIVE: To examine concussion symptoms and temporary academic accommodations during school use of a four-week student-centered return to learn (RTL) care plan. METHODS: Five public high schools used the RTL care plan and contributed student-level data after student report of concussion. Data on concussion symptoms, temporary academic accommodations corresponding to reported symptoms, and accommodations provided during RTL care plan use were examined. RESULTS: Of 115 students, 55%used the RTL care plan for three (34%) or four (21%) weeks. Compared to students whose symptoms resolve within the first two weeks, students who used the RTL care plan for three or four weeks reported more unique symptoms (P = 0.038), higher total severity score (P = 0.005), and higher average severity per symptom (P = 0.007) at week one. Overall, 1,127 weekly accommodations were provided. While least reported, emotional symptoms received corresponding accommodations most often (127/155 reports: 82%of occurrences). CONCLUSIONS: Use of an RTL care plan can facilitate the RTL of students with a concussion and may aid in the identification of students who are in need of longer-term support.

Modelling the Human Placental Interface In Vitro-A Review.

Acting as the primary link between mother and fetus, the placenta is involved in regulating nutrient, oxygen, and waste exchange; thus, healthy placental development is crucial for a successful pregnancy. In line with the increasing demands of the fetus, the placenta evolves throughout pregnancy, making it a particularly difficult organ to study. Research into placental development and dysfunction poses a unique scientific challenge due to ethical constraints and the differences in morphology and function that exist between species. Recently, there have been increased efforts towards generating in vitro models of the human placenta. Advancements in the differentiation of human induced pluripotent stem cells (hiPSCs), microfluidics, and bioprinting have each contributed to the development of new models, which can be designed to closely match physiological in vivo conditions. By including relevant placental cell types and control over the microenvironment, these new in vitro models promise to reveal clues to the pathogenesis of placental dysfunction and facilitate drug testing across the maternal-fetal interface. In this minireview, we aim to highlight current in vitro placental models and their applications in the study of disease and discuss future avenues for these in vitro models.

Mean Arterial Pressure and Discharge Outcomes in Severe Pediatric Traumatic Brain Injury.

BACKGROUND AND OBJECTIVE: Optimizing blood pressure is an important target for intervention following pediatric traumatic brain injury (TBI). The existing literature has examined the association between systolic blood pressure (SBP) and outcomes. Mean arterial pressure (MAP) is a better measure of organ perfusion than SBP and is used to determine cerebral perfusion pressure but has not been previously examined in relation to outcomes after pediatric TBI. We aimed to evaluate the strength of association between MAP-based hypotension early after hospital admission and discharge outcome and to contrast the relative strength of association of hypotension with outcome between MAP-based and SBP-based blood pressure percentiles. METHODS: We examined the association between lowest age-specific MAP percentile within 12 h after pediatric intensive care unit admission and poor discharge outcome (in-hospital death or transfer to a skilled nursing facility) in children with severe (Glasgow Coma Scale score < 9) TBI who survived at least 12 h. Poisson regression results were adjusted for maximum head Abbreviated Injury Scale (AIS) severity score, maximum nonhead AIS, and vasoactive medication use. We also examined the ability of lowest MAP percentile during the first 12 h to predict discharge outcomes using receiver operating curve characteristic analysis without adjustment for covariates. We contrasted the predictive ability and the relative strength of association of blood pressure with outcome between MAP and SBP percentiles. RESULTS: Data from 166 children aged < 18 years were examined, of whom 20.4% had a poor discharge outcome. Poor discharge outcome was most common among patients with lowest MAP < 5th percentile (42.9%; aRR 5.3 vs. 50-94th percentile, 95% CI 1.2, 23.0) and MAP 5-9th percentile (40%; aRR 8.5, 95% CI 1.9, 38.7). Without adjustment for injury severity or vasoactive medication use, lowest MAP percentile was moderately predictive of poor discharge outcome (AUC: 0.75, 95% CI 0.66, 0.85). In contrast, lowest SBP was associated with poor discharge outcome only for the < 5th percentile (50%; aRR 5.4, 95% CI 1.3, 22.2). Lowest SBP percentile was moderately predictive of poor discharge outcome (AUC: 0.82, 95% CI 0.74, 0.91). CONCLUSIONS: In children with severe TBI, a single MAP < 10th percentile during the first 12 h after Pediatric Intensive Care Unit admission was associated with poor discharge outcome. Lowest MAP percentile during the first 12 h was moderately predictive of poor discharge outcome. Lowest MAP percentile was more strongly associated with outcome than lowest SBP percentile but had slightly lower predictive ability than SBP.

Agreement Between Arterial Carbon Dioxide Levels With End-Tidal Carbon Dioxide Levels and Associated Factors in Children Hospitalized With Traumatic Brain Injury.

Importance: Alterations in the partial pressure of carbon dioxide, arterial (Paco2) can affect cerebral perfusion after traumatic brain injury. End-tidal carbon dioxide (EtCO2) monitoring is a noninvasive tool used to estimate Paco2 values. Objective: To examine the agreement between Paco2 and EtCO2 and associated factors in children with traumatic brain injury. Design, Setting, and Participants: A secondary analysis was conducted using data from a prospective cohort study of 137 patients younger than 18 years with traumatic brain injury who were admitted to the pediatric intensive care unit of a level I trauma center between May 1, 2011, and July 31, 2017. Analysis was performed from December 17, 2018, to January 10, 2019. Main Outcomes and Measures: The closest EtCO2 value obtained within 30 minutes of a Paco2 value and the closest systolic blood pressure value obtained within 60 minutes prior to a Paco2 value during the first 24 hours after admission were recorded. The main outcome of Paco2-EtCO2 agreement was defined as Paco2 between 0 and 5 mm Hg greater than the paired EtCO2 value, and it was determined using Bland-Altman analysis, Passing and Bablok regression, and the Pearson correlation coefficient. Multivariable regression models determined which factors were associated with agreement. Results: The analysis included 137 patients (34 girls and 103 boys; mean [SD] age, 10.0 [6.3] years) and 445 paired Paco2-EtCO2 data points. On average, Paco2 was 2.7 mm Hg (95% limits of agreement, -11.3 to 16.7) higher than EtCO2. Overall, 187 of all Paco2-EtCO2 pairs (42.0%) agreed. There was larger variation in the Paco2-EtCO2 difference during the first 8 hours compared with 9 to 24 hours after admission to the pediatric intensive care unit. Development of pediatric acute respiratory distress syndrome within 24 hours of admission was associated with a lower likelihood of Paco2-EtCO2 agreement (adjusted odds ratio, 0.20; 95% CI, 0.08-0.51) compared with no development of pediatric acute respiratory distress syndrome. A diagnosis of pediatric acute respiratory distress syndrome 1 to 7 days after admission was associated with a larger first-day Paco2-EtCO2 difference compared with those who never developed pediatric acute respiratory distress syndrome (mean [SD] difference, 4.48 [3.70] vs 0.46 [5.50] mm Hg). Conclusions and Relevance: In this study of pediatric traumatic brain injury, Paco2-EtCO2 agreement was low, especially among patients with pediatric acute respiratory distress syndrome. Low Paco2-EtCO2 agreement early in hospitalization may be associated with future development of pediatric acute respiratory distress syndrome. Data on EtCO2 should not be substituted for data on Paco2 during the first 24 hours.

The Pediatric Guideline Adherence and Outcomes (PEGASUS) programme in severe traumatic brain injury: a single-centre hybrid implementation and effectiveness study.

BACKGROUND: As far as we know, there are no tested in-hospital care programmes for paediatric traumatic brain injury. We aimed to assess implementation and effectiveness of the Pediatric Guideline Adherence and Outcomes (PEGASUS) programme in children with severe traumatic brain injury. METHODS: We did a prospective hybrid implementation and effectiveness study at the Harborview Medical Center (Seattle, WA, USA). We included children (aged <18 years) with traumatic brain injury (trauma mechanism and image findings). We assessed service provision, adherence to three key performance indicators, and discharge outcomes associated with the PEGASUS programme. The three key performance indicators were early initiation of enteral (oral or tube feeds) or parenteral nutrition; avoidance of any unwanted hypocarbia (PaCO2 <30 mm Hg) without brain herniation; and maintenance of cerebral perfusion pressure (>40 mm Hg) for 72 h after the diagnosis of severe traumatic brain injury. Poisson regression with robust standard errors was used to estimate the association between adhering to key performance indicators and discharge outcomes. FINDINGS: Between May 1, 2011, and July 1, 2017, 199 children (median age 11·9 years [IQR 3·4-16·1]) participated in the PEGASUS programme, of whom 193 (97%) had severe traumatic brain injury and six (3%) had moderate traumatic brain injury. 105 patients contributed data for all three key performance indicators. Adherence to at least one key performance indicator was achieved by 101 (96%) of 105 participants, and 44 (42%) achieved adherence to all three key performance indicators. Programme participants achieved adherence to the key performance indicators of hypocarbia (76 of 105 [72%]), nutrition (162 of 199 [81%]), and cerebral perfusion pressure (128 of 199 [64%]). Adherence to the nutrition key performance indicator was associated with higher discharge survival (relative risk [RR] 2·70, 95% CI 1·54-4·73) and a more favourable discharge disposition (3·05, 1·52-6·11). Adherence to the cerebral perfusion pressure key performance indicator was also associated with higher discharge survival (RR 1·33, 95% CI 1·12-1·59) and favourable disposition (1·53, 1·19-1·96). Adherence to each additional key performance indicator was associated with higher survival (RR 1·27, 1·12-1·44) and a more favourable discharge disposition (1·46, 1·23-1·72), in a dose-response manner. INTERPRETATION: The multilevel, hospital-wide, high-fidelity PEGASUS programme might benefit children and adolescents admitted to the emergency department with severe traumatic brain injury. Cerebral perfusion pressure, nutrition, and hypocarbia targets are essential components of the PEGASUS programme and are associated with favourable discharge outcomes. FUNDING: National Institutes of Health.

Huge traumatic pulmonary artery pseudoaneurysm.

Pulmonary artery pseudoaneurysm is a very rare complication of penetrating thoracic trauma. We present a case of a 27-year-old woman who developed a 6.5-cm traumatic pulmonary artery pseudoaneurysm after suffering multiple stab wounds to the chest and the abdomen. The pseudoaneurysm was successfully treated endovascularly with vascular plug occlusion and coil embolization.

Glenoid avulsion of the glenohumeral ligament (GAGL): a case report and review of the anatomy.

Shoulder dislocations are frequently seen in the general population and can be a cause of instability. Instability can lead to debilitating symptoms and morbidity as a result of progressive damage to the shoulder. Anterior shoulder dislocations are the most frequent type of dislocations and have been studied extensively with MRI. The soft tissue Bankart lesion is the most well-known entity associated with anterior instability; however, additional structural lesions arising from traumatic events have been described in recent literature which also predispose to anterior shoulder instability. One of these lesions, the glenoid avulsion of the glenohumeral ligament (GAGL), involves avulsion of the inferior glenohumeral ligament from the glenoid and involves separation from an intact labrum. In contrast to the Bankart lesion, there has been limited discussion of the GAGL lesion in the literature and very few imaging examples. We report a case of a GAGL diagnosed on MRI and confirmed with arthroscopy. It is discussed in the context of the anatomy of the inferior glenohumeral ligament and the imaging findings.

Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity.

Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.

Imidazo[2,1-b]thiazoles: multitargeted inhibitors of both the insulin-like growth factor receptor and members of the epidermal growth factor family of receptor tyrosine kinases.

The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.

Development of multitargeted inhibitors of both the insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor family of receptor tyrosine kinases.

Emerging clinical and pre-clinical data indicate that both insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor (EGF) family of receptor tyrosine kinases (RTKs) exhibit significant cross-talk in human cancers. Therefore, a small molecule that successfully inhibits the signaling of both classes of oncogenic kinases might provide an attractive agent for chemotherapeutic use. Herein, we disclose the structure activity relationships that led to the synthesis and biological characterization of 14, a novel small molecule inhibitor of both IGF-IR and members of the epidermal growth factor family of RTKs.

Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: a structural basis for the reduction of albumin binding.

Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening. These micromolar hits were rapidly improved to nanomolar leads on the basis of insights from protein crystallography; however, the compounds displayed extensive binding to human serum albumin and had limited activity in cellular assays. Modifications based on structural information on the binding of lead compounds to both MetAP2 and domain III of albumin allowed the identification of compounds with significant improvements in both parameters, which showed good cellular activity in both proliferation and methionine processing assays.

Development of sulfonamide compounds as potent methionine aminopeptidase type II inhibitors with antiproliferative properties.

We have screened molecules for inhibition of MetAP2 as a novel approach toward antiangiogenesis and anticancer therapy using affinity selection/mass spectrometry (ASMS) employing MetAP2 loaded with Mn(2+) as the active site metal. After a series of anthranilic acid sulfonamides with micromolar affinities was identified, chemistry efforts were initiated. The micromolar hits were quickly improved to potent nanomolar inhibitors by chemical modifications guided by insights from X-ray crystallography.

Methionine aminopeptidase 2 inhibition is an effective treatment strategy for neuroblastoma in preclinical models.

Tumor vascularity is correlated with an aggressive disease phenotype in neuroblastoma, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. We previously showed that the antiangiogenic compound TNP-470, an irreversible methionine aminopeptidase 2 (MetAP2) inhibitor, suppressed local and disseminated human neuroblastoma growth rates in murine models but had significant associated toxicity at the effective dose. We have recently shown that a novel, reversible MetAP2 inhibitor, A-357300, significantly inhibits CHP-134-derived neuroblastoma s.c. xenograft growth rate with a treatment-to-control (T/C) ratio at day 24 of 0.19 (P < 0.001) without toxicity. We now show that the combination of A-357300 with cyclophosphamide at the maximal tolerated dose sustained tumor regression with a T/C at day 48 of 0.16 (P < 0.001) in the CHP-134 xenograft model. A-357300 also significantly inhibited establishment and growth rate of hematogenous metastatic deposits following tail vein inoculation of CHP-134 cells and increased overall survival (P = 0.021). Lastly, A-357300 caused regression of established tumors in a genetically engineered murine model with progression-free survival in five of eight mice (P < 0.0001). There was no evidence of toxicity. These data show that MetAP2 may be an important molecular target for high-risk human neuroblastomas. We speculate that the growth inhibition may be through both tumor cell intrinsic and extrinsic (antiangiogenic) mechanisms. The potential for a wide therapeutic index may allow for treatment strategies that integrate MetAP2 inhibition with conventional cytotoxic compounds.

3-Amino-2-hydroxyamides and related compounds as inhibitors of methionine aminopeptidase-2.

Substituted 3-amino-2-hydroxyamides and related hydroxyamides and acylhydrazines were identified as inhibitors of human methionine aminopeptidase-2 (MetAP2). Examination of substituents through parallel synthesis and iterative structure-based design allowed the identification of potent inhibitors with good selectivity against MetAP1. Diacylhydrazine 3t (A-357300) was identified as an analogue displaying inhibition of methionine processing and cellular proliferation in human microvascular endothelial cells (HMVEC).

Tumor suppression by a rationally designed reversible inhibitor of methionine aminopeptidase-2.

Methionine aminopeptidase (MetAP)-2 has been suggested as a novel target for cancer therapy because the anticancer agent TNP-470 irreversibly inactivates the catalytic activity of this enzyme. However, the importance of MetAP2 in cell growth and tumor progression was uncertain because previous data were based on the chemically reactive TNP-470. Here we show that a rationally designed reversible MetAP2 inhibitor, A-357300, suppresses tumor growth preclinically without the toxicities observed with TNP-470. We have synthesized this bestatin-type MetAP2 inhibitor with the aid of crystal structures of the enzyme-inhibitor complexes and parallel synthesis. A-357300 induces cytostasis by cell cycle arrest at the G(1) phase selectively in endothelial cells and in a subset of tumor cells, but not in most primary cells of nonendothelial type. A-357300 inhibits angiogenesis both in vitro and in vivo and shows potent antitumor efficacy in carcinoma, sarcoma, and neuroblastoma murine models. These data affirm that MetAP2 plays a pivotal role in cell growth and establish that reversible MetAP2 inhibitors are promising novel cancer therapeutic agents.