Progesterone inactivation in decidual stromal cells: A mechanism for inflammation-induced parturition.

The process of human parturition involves inflammation at the interface where fetal chorion trophoblast cells interact with maternal decidual stromal (DS) cells and maternal immune cells in the decidua (endometrium of pregnancy). This study tested the hypothesis that inflammation at the chorion-decidua interface (CDI) induces labor by negating the capacity for progesterone (P4) to block labor and that this is mediated by inactivation of P4 in DS cells by aldo-keto reductase family 1 member C1 (AKR1C1). In human, Rhesus macaque, and mouse CDI, AKR1C1 expression increased in association with term and preterm labor. In a human DS cell line and in explant cultures of term human fetal membranes containing the CDI, the prolabor inflammatory cytokine, interleukin-1ß (IL-1ß), and media conditioned by LPS-stimulated macrophages increased AKR1C1 expression and coordinately reduced nuclear P4 levels and P4 responsiveness. Loss of P4 responsiveness was overcome by inhibition of AKR1C1 activity, inhibition of AKR1C1 expression, and bypassing AKR1C1 activity with a P4 analog that is not metabolized by AKR1C1. Increased P4 activity in response to AKR1C1 inhibition was prevented by the P4 receptor antagonist RU486. Pharmacologic inhibition of AKR1C1 activity prevented parturition in a mouse model of inflammation-induced preterm parturition. The data suggest that inflammatory stimuli at the CDI drive labor by inducing AKR1C1-mediated P4 inactivation in DS cells and that inhibiting and/or bypassing of AKR1C1-mediated P4 inactivation is a plausible therapeutic strategy to mitigate the risk of inflammation-associated preterm birth.

Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design.

IMPORTANCE: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER-Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. METHODS: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. DISCUSSION: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design.

Importance: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER- Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. Methods: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. Discussion: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. Registration: NCT05172024.

The urgent need for physician-led abortion advocacy.

When the Supreme Court of the United States decided Dobbs v. Jackson, it overruled Roe v. Wade and the decades of legal protections that physicians and patients have relied upon in making pregnancy decisions, including but not limited to abortion care. Abortion access has been limited before Dobbs, but the new legal landscape substantially limits patient access to abortion care by greatly curtailing legal provision of these services in many states, restricting physicians' ability to provide legal abortion care through confusing, inconsistent, and burdensome legal requirements, and by upending decades of reliable standards and leaving physicians and lawyers guessing about possible future court decision. Medical societies and healthcare organizations over the last 50 years since Roe have largely been silent in the face of attacks to abortion rights. Their silence left a void in which politicians and legislators without an understanding of abortion care promoted their own ideology and political interest at the expense of patient access to abortion care, patient autonomy, the physician-patient relationship, and physician autonomy. Physicians have an ethical duty to organize and advocate. Abortion legislation exemplifies the impact of unjust policies limiting our ability to provide patients with autonomy over their medical decision-making and interfering in the provision of evidence-based care, and in some cases preventing us from upholding our oath to do no harm. We must regain control of the examination room from political ideologies so that we can provide equitable, patient-centered, evidence-based, autonomous healthcare to our patients.

Tight vs liberal control of mild postpartum hypertension: a randomized controlled trial.

BACKGROUND: High-quality evidence to inform the management of postpartum hypertension, including the optimal blood pressure threshold to initiate therapy, is lacking. Randomized trials have been conducted in pregnancy, but there are no published trials to guide management in the postpartum period. OBJECTIVE: This study aimed to test the hypothesis that initiating antihypertensive therapy in the postpartum period at a threshold of 140/90 mm Hg would result in less maternal morbidity than initiating therapy at a threshold of 150/95 mm Hg. STUDY DESIGN: We performed a pragmatic multicenter randomized controlled trial of patients aged 18 to 55 years with postpartum hypertension. Patients with chronic hypertension, gestational hypertension, and preeclampsia without severe features were randomized to 1 of 2 blood pressure thresholds to initiate treatment: persistent blood pressure of ≥150/95 mm Hg (institutional standard or "liberal control" group) or ≥140/90 mm Hg (intervention or "tight control" group). Our primary outcome was composite maternal morbidity defined as: severe hypertension (blood pressure ≥160/110 mm Hg) or preeclampsia with severe features, the need for a second antihypertensive agent, postpartum hospitalization >4 days, and maternal adverse outcome secondary to hypertension as evidenced by pulmonary edema, acute kidney injury (creatinine level ≥1.1 mg/dL), cardiac dysfunction (eg, elevated brain natriuretic peptide level) or cardiomyopathy, posterior reversible encephalopathy syndrome, cerebrovascular accident, or admission to an intensive care unit. Secondary outcomes included hospital readmission for hypertension, persistence of hypertension beyond 14 days, medication side effects, and time to blood pressure control. We calculated that 256 women would provide 90% power to detect a relative 50% reduction in the primary outcome from 36% in the standard blood pressure threshold group to 18%, with a 2-sided alpha set at 0.05 for significance. Data were analyzed using R statistical software. RESULTS: A total of 256 patients were randomized, including 128 to the "tight control" group (140/90 mm Hg) and 128 to the "liberal control" group (150/95 mm Hg). Patients in the "tight control" group had a higher body mass index at delivery (37.1±9.4 vs 34.9±8.1; P=.04); other demographic and obstetrical characteristics were similar between groups. The rate of the primary outcome was similar between groups (8.6% vs 11.7%; P=.41; relative risk, 0.73; 95% confidence interval, 0.35-1.53). The rates of all secondary outcomes and the individual components of the primary and secondary outcome measures were also similar between groups. CONCLUSION: In the postpartum period, initiation of antihypertensive therapy at a lower blood pressure threshold of 140/90 mm Hg did not decrease maternal morbidity or improve outcomes compared with a threshold of 150/95 mm Hg.

Temporal Association Between Interracial Couples and Odds of Low Birth Weight Infants: Trends in National Vital Statistics Data from 1971 to 2016.

Our study explores the temporal association between low birth weight (LBW) infants and the increasing population prevalence of interracial relationships. Our hypothesis was that the odds of LBW would decrease as the population prevalence of interracial relationships increased. National Center for Health Statistics Natality data for 1971-2016 was analyzed. LBW was defined as birth weight less than 2500 gm. We restricted our analyses to singleton births by White and Black mothers with reported White or Black partners of the neonate. Logistic regression was used to calculate the odds ratios of LBW, both unadjusted and adjusted for maternal education and parental ages. The proportion of couples coded as interracial increased annually from 0.36% in 1971 to 3.86% in 2016 for White mothers and 0.59% to 8.63% for Black mothers during the same period. In each year the odds ratio of LBW was significant. As the proportion of White mothers with Black partners increased, their odds of LBW declined (OR1.75 to 1.30, p < 0.001). The odds ratio of LBW among Black mothers with White partners did not change and remained stable between 0.70 and 0.80 (p = 0.22) over the same time period. As the annual proportion of White mothers with Black partners increased, their odds of LBW decreased when compared to White couples. Black mothers with White partners did not exhibit a similar change when compared to Black couples, with the odds ratio of LBW remaining stable.

The impact of HBB-related hemoglobinopathies carrier status on fetal fraction in noninvasive prenatal screening.

OBJECTIVE: We evaluated whether there is an association between ß-globin (HBB) pathogenic variants and fetal fraction (FF), and whether the association has a clinically relevant impact on non-invasive prenatal screening (NIPS). METHOD: A whole-genome sequencing NIPS laboratory database was retrospectively queried for women who underwent NIPS and carrier screening of both HBB and the α-globin genes (HBA1/HBA2). Women affected with either condition were excluded from the study, yielding a cohort size of 15,853. A "corrected FF" was obtained via multivariable linear regression adjusted for the systematic impacts of maternal age, gestational age and BMI. Corrected FF distributions of HBB and HBA1/HBA2 carriers were each compared to non-carriers using the Kolmogorov-Smirnov test. RESULTS: In this cohort, 291 women were carriers for HBB alone, and 1016 were carriers for HBA1/HBA2 alone. The HBB carriers had a lower corrected FF when compared to non-carriers (p < 0.0001). There was no difference in corrected FF among carriers and non-carriers of HBA1/HBA2. CONCLUSION: Carriers of pathogenic variants in the HBB gene, but not the HBA1/HBA2 genes, are more likely to have lower FF when compared to women with structurally normal hemoglobin. This decrease in FF could result in an elevated test-failure rate if FF thresholds were used.

Improved estimates of strength and stiffness in pathologic vertebrae with bone metastases using CT-derived bone density compared with radiographic bone lesion quality classification.

OBJECTIVE: The aim of this study was to compare the ability of 1) CT-derived bone lesion quality (classification of vertebral bone metastases [BM]) and 2) computed CT-measured volumetric bone mineral density (vBMD) for evaluating the strength and stiffness of cadaver vertebrae from donors with metastatic spinal disease. METHODS: Forty-five thoracic and lumbar vertebrae were obtained from cadaver spines of 11 donors with breast, esophageal, kidney, lung, or prostate cancer. Each vertebra was imaged using microCT (21.4 µm), vBMD, and bone volume to total volume were computed, and compressive strength and stiffness experimentally measured. The microCT images were reconstructed at 1-mm voxel size to simulate axial and sagittal clinical CT images. Five expert clinicians blindly classified the images according to bone lesion quality (osteolytic, osteoblastic, mixed, or healthy). Fleiss' kappa test was used to test agreement among 5 clinical raters for classifying bone lesion quality. Kruskal-Wallis ANOVA was used to test the difference in vertebral strength and stiffness based on bone lesion quality. Multivariable regression analysis was used to test the independent contribution of bone lesion quality, computed vBMD, age, gender, and race for predicting vertebral strength and stiffness. RESULTS: A low interrater agreement was found for bone lesion quality (κ = 0.19). Although the osteoblastic vertebrae showed significantly higher strength than osteolytic vertebrae (p = 0.0148), the multivariable analysis showed that bone lesion quality explained 19% of the variability in vertebral strength and 13% in vertebral stiffness. The computed vBMD explained 75% of vertebral strength (p < 0.0001) and 48% of stiffness (p < 0.0001) variability. The type of BM affected vBMD-based estimates of vertebral strength, explaining 75% of strength variability in osteoblastic vertebrae (R2 = 0.75, p < 0.0001) but only 41% in vertebrae with mixed bone metastasis (R2 = 0.41, p = 0.0168), and 39% in osteolytic vertebrae (R2 = 0.39, p = 0.0381). For vertebral stiffness, vBMD was only associated with that of osteoblastic vertebrae (R2 = 0.44, p = 0.0024). Age and race inconsistently affected the model's strength and stiffness predictions. CONCLUSIONS: Pathologic vertebral fracture occurs when the metastatic lesion degrades vertebral strength, rendering it unable to carry daily loads. This study demonstrated the limitation of qualitative clinical classification of bone lesion quality for predicting pathologic vertebral strength and stiffness. Computed CT-derived vBMD more reliably estimated vertebral strength and stiffness. Replacing the qualitative clinical classification with computed vBMD estimates may improve the prediction of vertebral fracture risk.

Impact of Biases in Selection and Evaluation on the Composition of the Radiology Physician Workforce.

Lack of diversity in Radiology is a public health problem and may be self perpetuating as diverse candidates view the field as hostile to their entry and advancement, and consequently do not apply into the field. Solutions require understanding the obstacles, which range from enrollment in medical school to achieving leadership positions in Radiology. An understanding of the effect of demographic data on diversity in Radiology, disparate effects of Step examinations, medical school grades and induction into academic honor societies, and existing faculty disparities will allow us to better recruit, train, and retain a diverse group of physicians in our field. The downstream effect of a diverse workforce is improvement in health outcomes and disparities in medical care for our communities.

Large Lytic Defects Produce Kinematic Instability and Loss of Compressive Strength in Human Spines: An in Vitro Study.

BACKGROUND: In patients with spinal metastases, kinematic instability is postulated to be a predictor of pathologic vertebral fractures. However, the relationship between this kinematic instability and the loss of spinal strength remains unknown. METHODS: Twenty-four 3-level thoracic and lumbar segments from 8 cadaver spines from female donors aged 47 to 69 years were kinematically assessed in axial compression (180 N) and axial compression with a flexion or extension moment (7.5 Nm). Two patterns of lytic defects were mechanically simulated: (1) a vertebral body defect, corresponding to Taneichi model C (n = 13); and (2) the model-C defect plus destruction of the ipsilateral pedicle and facet joint, corresponding to Taneichi model E (n = 11). The kinematic response was retested, and compression strength was measured. Two-way repeated-measures analysis of variance was used to test the effect of each model on the kinematic response of the segment. Multivariable linear regression was used to test the association between the kinematic parameters and compressive strength of the segment. RESULTS: Under a flexion moment, and for both models C and E, the lesioned spines exhibited greater flexion range of motion (ROM) and axial translation than the control spines. Both models C and E caused lower extension ROM and greater axial, sagittal, and transverse translation under an extension moment compared with the control spines. Two-way repeated-measures analysis revealed that model E, compared with model C, caused significantly greater changes in extension and torsional ROM under an extension moment, and greater sagittal translation under a flexion moment. For both models C and E, greater differences in flexion ROM and sagittal translation under a flexion moment, and greater differences in extension ROM and in axial and transverse translation under an extension moment, were associated with lower compressive strength of the lesioned spines. CONCLUSIONS: Critical spinal lytic defects result in kinematic abnormalities and lower the compressive strength of the spine. CLINICAL RELEVANCE: This experimental study demonstrates that lytic foci degrade the kinematic stability and compressive strength of the spine. Understanding the mechanisms for this degradation will help to guide treatment decisions that address inferred instability and fracture risk in patients with metastatic spinal disease.

Role of C-reactive protein in effective utilization of emergent MRI for spinal infections.

PURPOSE: Emergent spinal MRI is recommended for patients with back pain and red flags for infection. However, many of these studies are negative due to low prevalence of spinal infections. Our purpose was to assess if C-reactive protein (CRP) can be used to guide effective utilization of emergent MRI for spinal infections. METHODS: 316/960 (33%) MRIs performed for infection by the emergency department over 75-month period had CRP levels obtained at presentation, after excluding patients receiving antibiotic or had spinal surgery in < 1 month. An MRI was considered positive when there was imaging evidence of spinal infection confirmed on follow-up by surgery/biopsy/drainage or definitive therapy. A CRP of ≤ 10 mg/L was considered normal and > 100 mg/L as highly elevated. RESULTS: CRP was normal in 95/316 (30%) and abnormal in 221/316 (70%) patients. MRI was positive in 43/316 (13.6%) patients, all of whom had abnormal CRP. CRP (p < 0.001) and intravenous drug use (IVDU; p = 0.002) were independently associated with a positive MRI. Receiver operator characteristic (ROC) analysis showed AUC of 0.76 for CRP, slightly improving with IVDU. Sensitivity, specificity, and negative predictive values for CRP level cut-off: 10 mg/L, 100%, 35%, and 100%, and 100 mg/L, 58%, 70% and 91%, respectively. CONCLUSION: Abnormal CRP, although extremely sensitive, lacks specificity in predicting a positive MRI for spinal infection unless highly elevated. However, a normal CRP (absent recent antibiotic or surgery) makes spinal infection unlikely, and its routine use as a screening test can help reducing utilization of emergent MRI for this purpose.

Automated Lateral Ventricular and Cranial Vault Volume Measurements in 13,851 Patients Using Deep Learning Algorithms.

BACKGROUND: No large dataset-derived standard has been established for normal or pathologic human cerebral ventricular and cranial vault volumes. Automated volumetric measurements could be used to assist in diagnosis and follow-up of hydrocephalus or craniofacial syndromes. In this work, we use deep learning algorithms to measure ventricular and cranial vault volumes in a large dataset of head computed tomography (CT) scans. METHODS: A cross-sectional dataset comprising 13,851 CT scans was used to deploy U-Net deep learning networks to segment and quantify lateral cerebral ventricular and cranial vault volumes in relation to age and sex. The models were validated against manual segmentations. Corresponding radiologic reports were annotated using a rule-based natural language processing framework to identify normal scans, cerebral atrophy, or hydrocephalus. RESULTS: U-Net models had high fidelity to manual segmentations for lateral ventricular and cranial vault volume measurements (Dice index, 0.878 and 0.983, respectively). The natural language processing identified 6239 (44.7%) normal radiologic reports, 1827 (13.1%) with cerebral atrophy, and 1185 (8.5%) with hydrocephalus. Age-based and sex-based reference tables with medians, 25th and 75th percentiles for scans classified as normal, atrophy, and hydrocephalus were constructed. The median lateral ventricular volume in normal scans was significantly smaller compared with hydrocephalus (15.7 vs. 82.0 mL; P < 0.001). CONCLUSIONS: This is the first study to measure lateral ventricular and cranial vault volumes in a large dataset, made possible with artificial intelligence. We provide a robust method to establish normal values for these volumes and a tool to report these on CT scans when evaluating for hydrocephalus.

Forecasting the impact of coronavirus disease during delivery hospitalization: an aid for resource utilization.

Background: The ongoing coronavirus disease 2019 pandemic has severely affected the United States. During infectious disease outbreaks, forecasting models are often developed to inform resource utilization. Pregnancy and delivery pose unique challenges, given the altered maternal immune system and the fact that most American women choose to deliver in the hospital setting. Objective: This study aimed to forecast the first pandemic wave of coronavirus disease 2019 in the general population and the incidence of severe, critical, and fatal coronavirus disease 2019 cases during delivery hospitalization in the United States. Study Design: We used a phenomenological model to forecast the incidence of the first wave of coronavirus disease 2019 in the United States. Incidence data from March 1, 2020, to April 14, 2020, were used to calibrate the generalized logistic growth model. Subsequently, Monte Carlo simulation was performed for each week from March 1, 2020, to estimate the incidence of coronavirus disease 2019 for delivery hospitalizations during the first pandemic wave using the available data estimate. Results: From March 1, 2020, our model forecasted a total of 860,475 cases of coronavirus disease 2019 in the general population across the United States for the first pandemic wave. The cumulative incidence of coronavirus disease 2019 during delivery hospitalization is anticipated to be 16,601 (95% confidence interval, 9711-23,491) cases, 3308 (95% confidence interval, 1755-4861) cases of which are expected to be severe, 681 (95% confidence interval, 1324-1038) critical, and 52 (95% confidence interval, 23-81) fatal. Assuming similar baseline maternal mortality rate as the year 2018, we projected an increase in maternal mortality rate in the United States to at least 18.7 (95% confidence interval, 18.0-19.5) deaths per 100,000 live births as a direct result of coronavirus disease 2019. Conclusion: Coronavirus disease 2019 in pregnant women is expected to severely affect obstetrical care. From March 1, 2020, we forecast 3308 severe and 681 critical cases with about 52 coronavirus disease 2019-related maternal mortalities during delivery hospitalization for the first pandemic wave in the United States. These results are significant for informing counseling and resource allocation.

Term Labor Outcomes after Cerclage Placement in a Multi-institutional Cohort.

OBJECTIVE: The placement of a cervical cerclage in early pregnancy could influence subsequent labor outcomes at term. Prior studies have yielded conflicting results regarding the potential association with adverse labor outcomes such as cesarean delivery (CD), cervical laceration, and prolonged labor. Our objective was to evaluate rate of CD and adverse maternal outcomes in women who labored at term with and without a cerclage within the Consortium on Safe Labor (CSL) cohort. We hypothesize that women with a cerclage in the incident pregnancy will have an increased frequency of CD and other adverse term labor outcomes. STUDY DESIGN: A retrospective cohort study was performed using data from the CSL. Women with live nonanomalous singleton gestations≥ 37 weeks with induced or spontaneous labor were identified. The risk of CD and other maternal and neonatal outcomes were compared between women with and without cerclage placement during pregnancy. Univariable and multivariable analyses were performed with adjustment for confounding factors. Planned subgroup analysis by history of CD was performed. RESULTS: A total of 374 of the 147,463 patients who met study inclusion criteria in the CSL (0.25%) had a cerclage. In univariable analysis, cerclage placement was associated with a significant increase in the frequency of CD (17.1 vs. 12.8%, p = 0.016, odds ratio: 1.4, 95% CI: 1.07-1.84), cervical lacerations, infectious morbidity, and blood loss. The association with CD persisted in multivariable regression. Cerclage placement was not associated with an increased risk of neonatal morbidity. CONCLUSION: Cerclage placement in pregnancy is associated with an increased risk of CD, cervical laceration, and infectious morbidity among women delivering at term. These findings suggest that cerclage placement may impact labor progression and outcomes. However, the magnitude of the association may not alter clinical decisions regarding cerclage placement in appropriate candidates.

The effects of metastatic lesion on the structural determinants of bone: Current clinical and experimental approaches.

Metastatic bone disease is incurable with an associated increase in skeletal-related events, particularly a 17-50% risk of pathologic fractures. Current surgical and oncological treatments are palliative, do not reduce overall mortality, and therefore optimal management of adults at risk of pathologic fractures presents an unmet medical need. Plain radiography lacks specificity and may result in unnecessary prophylactic fixation. Radionuclide imaging techniques primarily supply information on the metabolic activity of the tumor or the bone itself. Magnetic resonance imaging and computed tomography provide excellent anatomical and structural information but do not quantitatively assess bone matrix. Research has now shifted to developing unbiased data-driven tools that can predict risk of impending fractures and guide individualized treatment decisions. This review discusses the state-of-the-art in clinical and experimental approaches for prediction of pathologic fractures with bone metastases. Alterations in bone matrix quality are associated with an age-related increase in skeletal fragility but the impact of metastases on the intrinsic material properties of bone is unclear. Engineering-based analyses are non-invasive with the capability to evaluate oncological treatments and predict failure due to the progression of metastasis. The combination of these approaches may improve our understanding of the underlying deterioration in mechanical performance.

Comparison of Automated CT Perfusion Softwares in Evaluation of Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Automated imaging software is integral to decision-making in acute ischemic stroke (AIS) during extended time windows. RAPID software is the most widely used and has been validated in landmark endovascular trials. Olea software is another commercially available and FDA-approved software, but has not been studied in AIS trials. We aimed to compare the diagnostic utility and accuracy of RAPID and Olea in everyday clinical practice outside of a clinical trial. METHODS: We analyzed prospectively-collected data from a consecutive cohort of 141 patients with suspected AIS who underwent computed tomography perfusion upon presentation followed by diffusion-weighted magnetic resonance imaging (DWI-MRI) within 24-48 hours. Core infarct was defined as the region with a relative cerebral blood flow (rCBF) less than 30% on RAPID and rCBF less than 40% on Olea (default settings). We also evaluated rCBF less than 30% on Olea to match RAPID's default setting. Infarct volume on DWI-MRI was measured using a semiautomated segmentation method. RESULTS: Twenty-one patients were excluded; 14 due to poor bolus tracking and/or motion artifact, and 7 due to software failure. The software failure rate was 4.7% [6/127] with RAPID versus .78% [1/127] with Olea (P = .12). For the remaining 120 patients, the sensitivity and specificity for detecting an acute infarct were 40.5% and 97.6% for RAPID; 50.6% and 85.4% for Olea; and for detecting large infarcts (≥70 mL on DWI-MRI) 73.7% and 81.2% for RAPID; 73.7% and 68.3% for Olea. Core infarct volume on RAPID was more closely correlated with DWI-MRI infarct volume (rho = .64) than Olea (rho = .42). CONCLUSIONS: Our head-to-head comparison of these 2 commonly-used softwares in the clinical setting elucidates the pros and cons of their use to guide decision-making for AIS management in the acute setting.

GTP hydrolysis promotes disassembly of the atlastin crossover dimer during ER fusion.

Membrane fusion of the ER is catalyzed when atlastin GTPases anchored in opposing membranes dimerize and undergo a crossed over conformational rearrangement that draws the bilayers together. Previous studies have suggested that GTP hydrolysis triggers crossover dimerization, thus directly driving fusion. In this study, we make the surprising observations that WT atlastin undergoes crossover dimerization before hydrolyzing GTP and that nucleotide hydrolysis and Pi release coincide more closely with dimer disassembly. These findings suggest that GTP binding, rather than its hydrolysis, triggers crossover dimerization for fusion. In support, a new hydrolysis-deficient atlastin variant undergoes rapid GTP-dependent crossover dimerization and catalyzes fusion at an initial rate similar to WT atlastin. However, the variant cannot sustain fusion activity over time, implying a defect in subunit recycling. We suggest that GTP binding induces an atlastin conformational change that favors crossover dimerization for fusion and that the input of energy from nucleotide hydrolysis promotes complex disassembly for subunit recycling.

Female Human Spines with Simulated Osteolytic Defects: CT-based Structural Analysis of Vertebral Body Strength.

Purpose To evaluate a CT structural analysis protocol (SAP) for estimating the strength of human female cadaveric spines with lytic lesions. Materials and Methods Osteolytic foci was created in the middle vertebra of 44 thoracic and lumbar three-level segments from 11 female cadavers (age range, 50-70 years). The segments underwent CT by using standard clinical protocol and their failure strength was assessed at CT SAP. The spines were mechanically tested to failure in pure axial compression or in compression with torsion. The relationships of defect size, bone mineral density, and predicted failure load (at CT SAP) with measured vertebral strength were assessed with linear regression. Analysis of variance and Tukey test were used to evaluate the effect of region and mechanical test on spine strength. Results With axial compression, CT SAP predictions of vertebral strength correlated with the thoracic (r = 0.84; P < .001) and lumbar (r = 0.85; P < .001) segment-measured strength. Bone mineral density correlated with the lumbar (r = 0.64; P = .003) and thoracic (r, 0.51; P = .050) strength. At compression with torsion, CT SAP predictions of strength were moderately correlated with vertebral strength (r = 0.66; P = .018). At compression with torsion, bone mineral density was not correlated with spinal strength (thoracic and lumbar: r = 0.31 and r = 0.26, respectively; P = .539 and .610, respectively). The lytic focus size (range, 28%-41%) was not associated with vertebral strength. Conclusion CT SAP assessment of strength in vertebrae with lytic lesions correlated with the measured strength of female vertebral bodies. © RSNA, 2018 Online supplemental material is available for this article.

Integrating MRI-based geometry, composition and fiber architecture in a finite element model of the human intervertebral disc.

Intervertebral disc degeneration is a common disease that is often related to impaired mechanical function, herniations and chronic back pain. The degenerative process induces alterations of the disc's shape, composition and structure that can be visualized in vivo using magnetic resonance imaging (MRI). Numerical tools such as finite element analysis (FEA) have the potential to relate MRI-based information to the altered mechanical behavior of the disc. However, in terms of geometry, composition and fiber architecture, current FE models rely on observations made on healthy discs and might therefore not be well suited to study the degeneration process. To address the issue, we propose a new, more realistic FE methodology based on diffusion tensor imaging (DTI). For this study, a human disc joint was imaged in a high-field MR scanner with proton-density weighted (PD) and DTI sequences. The PD image was segmented and an anatomy-specific mesh was generated. Assuming accordance between local principal diffusion direction and local mean collagen fiber alignment, corresponding fiber angles were assigned to each element. Those element-wise fiber directions and PD intensities allowed the homogenized model to smoothly account for composition and fibrous structure of the disc. The disc's in vitro mechanical behavior was quantified under tension, compression, flexion, extension, lateral bending and rotation. The six resulting load-displacement curves could be replicated by the FE model, which supports our approach as a first proof of concept towards patient-specific disc modeling.