Evidence-Based Update on Transcatheter Therapies for Pulmonary Embolism.

PURPOSE OF REVIEW: Pulmonary embolism (PE) remains a leading cause of cardiovascular morbidity and mortality. Multiple new therapies are in development and under study to improve our contemporary care of patients with PE. We review and compare here these novel therapeutics and technologies. RECENT FINDINGS: Multiple novel therapeutic devices have been developed and are under active study. This work has advanced the care of patients with intermediate and high-risk PE. Novel therapies are improving care of complex PE patients. These have inspired large multicenter international randomized controlled trials that are actively recruiting patients to advance the care of PE. These studies will work towards advancing guidelines for clinical care of patients with PE.

The influence of pelvic tilt on sacral insufficiency fracture occurrence: Insights into the prevalence of high pelvic tilt among patients affected.

INTRODUCTION: Fragility fractures without significant trauma of the pelvic ring in older patients have an increasing incidence due to demographic change. Influencing factors other than osteoporotic bone quality that lead to an insufficiency fracture are not yet known. However, it is suspected that the pelvic tilt (PT) has an effect on the development of such an insufficiency fracture. This study explores the influence of the PTs in patients with insufficiency fractures of the posterior pelvic ring. MATERIALS AND METHODS: A total of 49 geriatric patients with fragility fractures of the pelvic ring were treated at a university hospital level-1 trauma center during a period between February and December 2023, and their fractures were classified according to the FFP classification of Rommens and Hofmann. Complete sets of computer tomography (CT) and radiological images were available to determine the PT angle of the patients. RESULTS: 34 FFP type 2 and 15 FFP type 3 classified patients were included in the study. Significant difference was seen in the pelvic tilt (PT) angle between the patient group with insufficiency fractures (n= 49; mean age: 78.02 ± 11.80) and the control group with lumbago patients (n= 53; mean age: 69.23 ± 11.23). The PT was significantly higher in the patients with insufficiency fractures (25.74° ± 4.76; p⁎⁎⁎⁎ ≤ 0.0001). CONCLUSIONS: The study demonstrates a significant extension of the PT angle of individuals with insufficiency fractures when compared to those with lumbago. The result suggests a potential association between pelvic tilt and fracture susceptibility. TRIAL REGISTRATION: A retrospective study about the influence of sagittal balance of the spine on insufficiency fractures of the posterior pelvic ring measured by the "pelvic tilt angle", DRKS00032120. Registered 20th June 2023 - Prospectively registered. Trial registration number DRKS00032120.

Angiographic Coronary Slow Flow Is Not a Valid Surrogate for Invasively Diagnosed Coronary Microvascular Dysfunction.

BACKGROUND: Ischemia with no obstructive coronary arteries is frequently caused by coronary microvascular dysfunction (CMD). Consensus diagnostic criteria for CMD include baseline angiographic slow flow by corrected TIMI (Thrombolysis In Myocardial Infarction) frame count (cTFC), but correlations between slow flow and CMD measured by invasive coronary function testing (CFT) are uncertain. OBJECTIVES: The aim of this study was to investigate relationships between cTFC and invasive CFT for CMD. METHODS: Adults with ischemia with no obstructive coronary arteries underwent invasive CFT with thermodilution-derived baseline coronary blood flow, coronary flow reserve (CFR), and index of microcirculatory resistance (IMR). CMD was defined as abnormal CFR (<2.5) and/or abnormal IMR (≥25). cTFC was measured from baseline angiography; slow flow was defined as cTFC >25. Correlations between cTFC and baseline coronary flow and between CFR and IMR and associations between slow flow and invasive measures of CMD were evaluated, adjusted for covariates. All patients provided consent. RESULTS: Among 508 adults, 49% had coronary slow flow. Patients with slow flow were more likely to have abnormal IMR (36% vs 26%; P = 0.019) but less likely to have abnormal CFR (28% vs 42%; P = 0.001), with no difference in CMD (46% vs 51%). cTFC was weakly correlated with baseline coronary blood flow (r = -0.35; 95% CI: -0.42 to -0.27), CFR (r = 0.20; 95% CI: 0.12 to 0.28), and IMR (r = 0.16; 95% CI: 0.07-0.24). In multivariable models, slow flow was associated with lower odds of abnormal CFR (adjusted OR: 0.53; 95% CI: 0.35 to 0.80). CONCLUSIONS: Coronary slow flow was weakly associated with results of invasive CFT and should not be used as a surrogate for the invasive diagnosis of CMD.

A Mechanistic and Preclinical Assessment of BioRestore Bioactive Glass as a Synthetic Bone Graft Extender and Substitute for Osteoinduction and Spine Fusion.

STUDY DESIGN: Preclinical animal study. OBJECTIVE: Evaluate the osteoinductivity and bone regenerative capacity of BioRestore bioactive glass. SUMMARY OF BACKGROUND DATA: BioRestore is a Food and Drug Administration (FDA)-approved bone void filler that has not yet been evaluated as a bone graft extender or substitute for spine fusion. METHODS: In vitro and in vivo methods were used to compare BioRestore with other biomaterials for the capacity to promote osteodifferentiation and spinal fusion. The materials evaluated (1) absorbable collagen sponge (ACS), (2) allograft, (3) BioRestore, (4) Human Demineralized Bone Matrix (DBM), and (5) MasterGraft. For in vitro studies, rat bone marrow-derived stem cells (BMSC) were cultured on the materials in either standard or osteogenic media (SM, OM), followed by quantification of osteogenic marker genes (Runx2, Osx, Alpl, Bglap, Spp1) and alkaline phosphatase (ALP) activity. Sixty female Fischer rats underwent L4-5 posterolateral fusion (PLF) with placement of 1 of 5 implants: (1) ICBG from syngeneic rats; (2) ICBG+BioRestore; (3) BioRestore alone; (4) ICBG+Allograft; or (5) ICBG+MasterGraft. Spines were harvested 8 weeks postoperatively and evaluated for bone formation and fusion via radiography, blinded manual palpation, microCT, and histology. RESULTS: After culture for 1 week, BioRestore promoted similar expression levels of Runx2 and Osx to cells grown on DBM. At the 2-week timepoint, the relative ALP activity for BioRestore-OM was significantly higher (P<0.001) than that of ACS-OM and DBM-OM (P<0.01) and statistically equivalent to cells grown on allograft-OM. In vivo, radiographic and microCT evaluation showed some degree of bridging bone formation in all groups tested, with the exception of BioRestore alone, which did not produce successful fusions. CONCLUSIONS: This study demonstrates the capacity of BioRestore to promote osteoinductivity in vitro. In vivo, BioRestore performed similarly to commercially available bone graft extender materials but was incapable of producing fusion as a bone graft substitute. LEVEL OF EVIDENCE: Level V.

Cardiogenic Shock Intravascular Cooling Trial (CHILL-SHOCK).

BACKGROUND: Cardiogenic shock (CS) is complicated by high mortality rates. Targeted temperature control (TTC) has been proposed as an adjunct therapy in CS. This study aims to examine the safety of TTC in patients presenting with CS. METHODS AND RESULTS: In this open-label, randomized controlled pilot trial, 20 patients with hemodynamic criteria for CS were assigned to standard of care plus TTC vs standard of care alone. The primary outcome was a composite safety outcome, including well-described complications of TTC. Secondary outcomes included mortality at 90 days, invasive hemodynamic and echocardiographic parameters, electrocardiographic measurements, and inotrope dosing. There were no significant differences in the composite analysis of prespecified safety outcomes (3 events in the TTC group vs 0 events in the control group; P = 0.24). Patients randomized to TTC demonstrated a statistically significant increase in cardiac index and cardiac power index compared to the control group at 48-96 hours after randomization (3.6 [3.1, 3.9] L/min/m2 vs 2.6 [2.5, 3.15] L/min/m2; P = 0.029 and 0.61 [0.55, 0.7] W/m2 vs 0.53 [0.435, 0.565] W/m2; P = 0.029, respectively). CONCLUSION: TTC may be a safe adjunct therapy for patients presenting with CS and may yield improvement in specific hemodynamic parameters.

Regulation of 20α-Hydroxysteroid Dehydrogenase Expression in Term Pregnant Human Myometrium Ex Vivo.

Metabolic inactivation of progesterone within uterine myocytes by 20α-hydroxysteroid dehydrogenase (20α-HSD) has been postulated as a mechanism contributing to functional progesterone withdrawal at term. In humans, 20α-HSD is encoded by the gene AKR1C1. Myometrial AKR1C1 mRNA abundance has been reported to increase significantly during labor at term. In spontaneous preterm labor, however, we previously found no increase in AKR1C1 mRNA level in the myometrium except for preterm labor associated with clinical chorioamnionitis. This suggests that increased 20α-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labor. In this study, we have determined the effects of various treatments of therapeutic relevance on AKR1C1 expression in pregnant human myometrium in an ex vivo culture system. AKR1C1 expression increased spontaneously during 48 h culture (p < 0.0001), consistent with the myometrium transitioning to a labor-like phenotype ex vivo, as reported previously. Serum supplementation, prostaglandin F2α, phorbol myristate acetate, and mechanical stretch had no effect on the culture-induced increase, whereas progesterone (p = 0.0058) and cAMP (p = 0.0202) further upregulated AKR1C1 expression. In contrast, culture-induced upregulation of AKR1C1 expression was dose-dependently repressed by three histone/protein deacetylase inhibitors: trichostatin A at 5 (p = 0.0172) and 25 µM (p = 0.0115); suberoylanilide hydroxamic acid at 0.5 (p = 0.0070), 1 (p = 0.0045), 2.5 (p = 0.0181), 5 (p = 0.0066) and 25 µM (p = 0.0014); and suberoyl bis-hydroxamic acid at 5 (p = 0.0480) and 25 µM (p = 0.0238). We propose the inhibition of histone/protein deacetylation helps to maintain the anti-inflammatory, pro-quiescence signaling of progesterone in pregnant human myometrium by blocking its metabolic inactivation. Histone deacetylase inhibitors may represent a class of agents that preserve or restore the progesterone sensitivity of the pregnant uterus.

Effects of Iliosacral Joint Immobilization on Walking after Iliosacral Screw Fixation in Humans.

BACKGROUND: Pelvis fractures are commonly stabilized by surgical implants to facilitate their healing. However, such implants immobilize the iliosacral joint for up to a year until removal. We report how iliosacral joint immobilization affects the walking of patients. METHODS: The gaits of patients with immobilized sacroiliac joints after unstable pelvic fracture (n = 8; mean age: 45.63 ± 23.19; five females and three males) and sex- and age-matched healthy control individuals (n = 8; mean age: 46.50 ± 22.91; five females and three males) were recorded and analyzed using a motion capture system. The forces between the tread and feet were also recorded. Standard gait parameters as well as dynamic patterns of joint angles and moments of the lower extremities were analyzed using the simulation software OpenSim. RESULTS: With the exception of hip extensor strength, the monitored joint parameters of the patients showed task-dependent deviations during walking, i.e., plantarflexor force was increased when stepping on an elevated surface, as were hip flexion and extensor moments, knee flexion and extensor moments, as well as ankle dorsiflexion and the associated negative plantarflexor force during stance on the elevated surface. CONCLUSIONS: Iliosacral joint fixation causes reduced forward and upward propulsion and requires an extended range of hip motion in the sagittal plane. Patients show significant mobility limitation after iliosacral screw fixation.

Effects of inflammation on thrombosis and outcomes in COVID-19: secondary analysis of the ATTACC/ACTIV-4a trial.

Background: Patients hospitalized for COVID-19 are at high risk of thrombotic complications and organ failure, and often exhibit severe inflammation, which may contribute to hypercoagulability. Objectives: To determine whether patients hospitalized for COVID-19 experience differing frequencies of thrombotic and organ failure complications and derive variable benefits from therapeutic-dose heparin dependent on the extent of systemic inflammation and whether observed benefit from therapeutic-dose anticoagulation varies depending on the degree of systemic inflammation. Methods: We analyzed data from 1346 patients hospitalized for COVID-19 enrolled in the ATTACC and ACTIV-4a platforms who were randomized to therapeutic-dose heparin or usual care for whom levels of C-reactive protein (CRP) were reported at baseline. Results: Increased CRP was associated with worse patient outcomes, including a >98% posterior probability of increased organ support requirement, hospital length of stay, risk of 28-day mortality, and incidence of major thrombotic events or death (patients with CRP 40-100 mg/L or ≥100 mg/L compared to patients with CRP <40 mg/L). Patients with CRP 40 to 100 mg/L experienced the greatest degree of benefit from treatment with therapeutic doses of unfractionated or low molecular weight heparin compared with usual-care prophylactic doses. This was most significant for an increase in organ support-free days (odds ratio: 1.63; 95% confidence interval, 1.09-2.40; 97.9% posterior probability of beneficial effect), with trends toward benefit for other evaluated outcomes. Conclusion: Moderately ill patients hospitalized for COVID-19 with CRP between 40 mg/L and 100 mg/L derived the greatest benefit from treatment with therapeutic-dose heparin.

[Information on Death Certificates: Comparison Between Inpatient and Outpatient Sectors]. / Angaben auf Todesbescheinigungen ­ Vergleich des hospitalen und ambulanten Bereichs.

The death of a person and the circumstances of death are documented on the death certificate in Germany. The path of the corpse to burial as well as the quality of the cause of death statistics are significantly influenced by the information in the official death certificate. The quality of the information in the death certificates has been repeatedly criticized. The aim of the present study was to identify typical sources of error in death certificates and to obtain information on whether qualitative differences exist between death certificates completed in the outpatient and inpatient sectors. A retrospective evaluation was performed of 218 death certificates of deaths examined by the Institute of Legal Medicine as part of a second postmortem examination prior to cremation. Of these, 118 death certificates were issued in the hospital and 100 death certificates were issued on an outpatient basis by the family physician or a physician on duty in the outpatient sector. All but one of the death certificates issued on an outpatient basis were legible. The information on the underlying disease was plausible. More than one-third of the epicrises had no significant findings or were not completed at all. The entry on the immediate causes of death in the designated field on the death certificate (Ia in the causal chain) were inadequate in one third of the cases. The error rate in the entries was higher in outpatient than in inpatient deaths. In the future, therefore, it will be necessary to prepare for the special situation of a post-mortem examination by means of further and advanced training events and to convey the importance of the diagnoses determined in the process, in order to eliminate these avoidable sources of error.

Cervical Disc Arthroplasties Fail to Maintain Physiological Kinematics Under Lateral Eccentric Loads.

STUDY DESIGN: In vitro human cadaveric biomechanical analysis. OBJECTIVES: Optimization of prostheses for cervical disc arthroplasties (CDA) reduces the risk of complications. The instantaneous helical axis (IHA) is a superior parameter for examining the kinematics of functional spinal units. There is no comprehensive study about the IHA after CDA considering all 3 motion dimensions. METHODS: Ten human functional spinal units C4-5 (83.2 ± 7.9 yrs.) were examined with an established measuring apparatus in intact conditions (IC), and after CDA, with 2 different types of prostheses during axial rotation, lateral bending, and flexion/extension. Eccentric preloads simulated strains. The IHA orientation and its position at the point of rest (IHA0-position) were analyzed. RESULTS: The results confirmed the existing data for IHA in IC. Lateral preloads showed structural alterations of kinematics after CDA: During axial rotation and lateral bending, the shift of the IHA0-position was corresponding with the lateral preloads' applied site in IC, while after CDAs, it was vice versa. During lateral bending, the lateral IHA orientation was inclined, corresponding with the lateral preloads' applied site in the IC and oppositely after the CDAs. During flexion/extension, the lateral IHA orientation was nearly vertical in the IC, while after CDA, it inclined, corresponding with the lateral preloads' applied site. The axial IHA orientation rotated to the lateral preloads' corresponding site in the IC; after CDA, it was vice versa. CONCLUSION: Both CDAs failed to maintain physiological IHA characteristics under lateral preloads, revealing a new aspect for improving prostheses' design and optimizing their kinematics.

Use of Intravascular Ultrasound and Coronary Angiography to Measure the Prevalence of Myocardial Bridge in Heart Transplant Patients.

Myocardial bridge (MB) detection rates vary across methods and most studies that have assessed MB include symptomatic patients. Intravascular ultrasound (IVUS) is a sensitive tool for MB detection and donor hearts may serve as a surrogate measure of asymptomatic patients. We used IVUS and coronary angiography to measure MB prevalence in heart transplant patients during routine follow-up invasive coronary assessments. This was a retrospective, single-center study of heart transplant patients who received follow-up coronary assessments at the University of Chicago Heart and Vascular Center between December 2014 and December 2021. A single experienced interventional cardiologist assessed incidental findings of MB in IVUS and coronary angiography. Detection rates were compared with meta-analysis-reported prevalence. Of 129 patients, IVUS-detected MB in 87 patients (67.4%), whereas coronary angiography detected 41 (31.8%). All MB found by coronary angiography were detected by IVUS. Some level of cardiac allograft vasculopathy was found in 92 patients (71.3%). Our IVUS-detected MB prevalence was greater than meta-analysis-reported pooled prevalence across all methods: autopsy, computed tomography angiography, and coronary angiography (67.4% [95% confidence interval [CI] 59.4 to 75.5] vs 42% [95% CI 30 to 55]; 22% [95% CI 18 to 25]; 6% [95% CI 5 to 8], p ≤0.005). The difference between our observed IVUS-detected MB prevalence and meta-analysis autopsy reported MB prevalence was 1.25 (95% CI 1.11 to 1.40). In conclusion, the high prevalence of MB recorded in donor hearts emphasizes the need to further investigate the causes of chest pain in patients who are found to have MB.

Clopidogrel Administration Impairs Post-Stroke Learning and Memory Recovery in Mice.

Clopidogrel, which is one of the most prescribed antiplatelet medications in the world, is given to stroke survivors for the prevention of secondary cardiovascular events. Clopidogrel exerts its antiplatelet activity via antagonism of the P2Y12 receptor (P2RY12). Although not widely known or considered during the initial clinical trials for clopidogrel, P2RY12 is also expressed on microglia, which are the brain's immune cells, where the receptor facilitates chemotactic migration toward sites of cellular damage. If microglial P2RY12 is blocked, microglia lose the ability to migrate to damaged sites and carry out essential repair processes. We aimed to investigate whether administering clopidogrel to mice post-stroke was associated with (i) impaired motor skills and cognitive recovery; (ii) physiological changes, such as survival rate and body weight; (iii) changes in the neurovascular unit, including blood vessels, microglia, and neurons; and (iv) changes in immune cells. Photothrombotic stroke (or sham surgery) was induced in adult male mice. From 24 h post-stroke, mice were treated daily for 14 days with either clopidogrel or a control. Cognitive performance (memory and learning) was assessed using a mouse touchscreen platform (paired associated learning task), while motor impairment was assessed using the cylinder task for paw asymmetry. On day 15, the mice were euthanized and their brains were collected for immunohistochemistry analysis. Clopidogrel administration significantly impaired learning and memory recovery, reduced mouse survival rates, and reduced body weight post-stroke. Furthermore, clopidogrel significantly increased vascular leakage, significantly increased the number and appearance of microglia, and significantly reduced the number of T cells within the peri-infarct region post-stroke. These data suggest that clopidogrel hampers cognitive performance post-stroke. This effect is potentially mediated by an increase in vascular permeability post-stroke, providing a pathway for clopidogrel to access the central nervous system, and thus, interfere in repair and recovery processes.

Increases in adolescent firearm injuries were associated with school closures during COVID-19.

BACKGROUND: Mitigation measures, including school closures, were enacted to protect the public during the COVID-19 pandemic. However, the negative effects of mitigation measures are not fully known. Adolescents are uniquely vulnerable to policy changes since many depend on schools for physical, mental, and/or nutritional support.  This study explores the statistical relationships between school closures and adolescent firearm injuries (AFI) during the pandemic. METHODS: Data were drawn from a collaborative registry of 4 trauma centers in Atlanta, GA (2 adult and 2 pediatric). Firearm injuries affecting adolescents aged 11-21 years from 1/1/2016 to 6/30/2021 were evaluated. Local economic and COVID data were obtained from the Bureau of Labor Statistics and the Georgia Department of Health. Linear models of AFI were created based on COVID cases, school closure, unemployment, and wage changes. RESULTS: There were 1,330 AFI at Atlanta trauma centers during the study period, 1,130 of whom resided in the 10 metro counties. A significant spike in injuries was observed during Spring 2020. A season-adjusted time series of AFI was found to be non- stationary (p = 0.60). After adjustment for unemployment, seasonal variation, wage changes, county baseline injury rate, and county-level COVID incidence, each additional day of unplanned school closure in Atlanta was associated with 0.69 (95% CI 0.34- 1.04, p < 0.001) additional AFIs across the city. CONCLUSION: AFI increased during the COVID pandemic. This rise in violence is statistically attributable in part to school closures after adjustment for COVID cases, unemployment, and seasonal variation. These findings reinforce the need to consider the direct implications on public health and adolescent safety when implementing public policy.

Dupilumab Improves Outcomes in Patients with Chronic Rhinosinusitis with Nasal Polyps and Coexisting Asthma Irrespective of Baseline Asthma Characteristics.

Purpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease frequently coexisting with other type 2 conditions including asthma and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Coexisting asthma leads to increased CRSwNP symptom burden. Dupilumab, a monoclonal antibody that blocks the shared receptor component for interleukin-4 and -13, demonstrated efficacy in adults with severe CRSwNP in the Phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies, including in patients with coexisting asthma/NSAID-ERD. However, the impact of different asthma characteristics on dupilumab treatment in this population is unknown. We report CRSwNP and asthma outcomes with dupilumab in patients with CRSwNP and coexisting asthma according to baseline asthma characteristics. Methods: Change from baseline at Week 24 (pooled studies) and Week 52 (SINUS-52) in CRSwNP outcomes (nasal polyp score, nasal congestion, 22-item Sino-Nasal Outcome Test [SNOT-22], loss of smell score, University of Pennsylvania Smell Identification Test) and asthma outcomes (5-item Asthma Control Questionnaire [ACQ-5], pre-bronchodilator forced expiratory volume in 1 second [FEV1]) were analyzed post hoc for placebo and dupilumab 300 mg every 2 weeks according to baseline blood eosinophils ≥150/≥300 cells/µL, ACQ-5 scores <1.5/≥1.5, and FEV1 <80%. Results: In the pooled studies, 428/724 patients (59.1%) had coexisting asthma, of which 181/428 (42.3%) had coexisting NSAID-ERD. Dupilumab significantly improved all CRSwNP and asthma outcomes vs placebo at Week 24 (P < 0.001) regardless of baseline eosinophil or ACQ-5 category, or FEV1 <80%. Similar magnitude of improvement was seen at Week 52 (SINUS-52) and in patients with NSAID-ERD (pooled studies, Week 24). By Week 24, improvements with dupilumab exceeded the minimum clinically important differences for ACQ-5 and SNOT-22 in 35.2% to 74.2% and 72.0% to 78.7% of patients, respectively. Conclusion: Dupilumab improved CRSwNP outcomes in patients with CRSwNP and coexisting asthma, and improved asthma outcomes, regardless of differences in baseline asthma characteristics.

Effect of a Contrast Agent on Bone Mineral Density Measurement in the Spine and Hip Using QCT-Conversion Factor Recommendation.

BACKGROUND: Osteoporosis causes an increased fracture risk. Clinically, osteoporosis is diagnosed late, usually after the first fracture occurs. This emphasizes the need for an early diagnosis of osteoporosis. However, computed tomography (CT) as routinely used for polytrauma scans cannot be used in the form of quantitative computed tomography (QCT) diagnosis because QCT can only be applied natively, i.e., without any contrast agent application. Here, we tested whether and how contrast agent application could be used for bone densitometry measurements. METHODS: Bone mineral density (BMD) was determined by QCT in the spine region of patients with and without the contrast agent Imeron 350. Corresponding scans were performed in the hip region to evaluate possible location-specific differences. RESULTS: Measurements with and without contrast agent administration between spine and hip bones indicate that the corresponding BMD values were reproducibly different between spine and hips, indicating that Imeron 350 application has a location-specific effect. We determined location-specific conversion factors that allow us then to determine the BMD values relevant for osteoporosis diagnosis. CONCLUSIONS: Results show that contrast administration cannot be used directly for CT diagnostics because the agent significantly alters BMD values. However, location-specific conversion factors can be established, which are likely to depend on additional parameters such as the weight and corresponding BMI of the patient.

Physiological Femoral Condylar Morphology in Adult Knees-A MRI Study of 517 Patients.

BACKGROUND: In the age of individualised arthroplasty, the question arises whether currently available standard implants adequately consider femoral condylar morphology (FCM). Therefore, physiological reference values of FCM are needed. The aim was to establish physiological reference values for anterior (ACO) and posterior condylar offset (PCO) as well as for the length of the medial (LMC) and lateral femoral condyles (LLC). METHODS: The knee joints of 517 patients (mean age: 52.3 years (±16.8)) were analysed retrospectively using MRI images. Medial (med) and lateral (lat) ACO and PCO, as well as LMC and LLC, were measured. All FCM parameters were examined for association with age, gender, side and osteoarthritis. RESULTS: Mean ACOmed was 2.8 mm (±2.5), mean ACOlat was 6.7 mm (±2.3), mean PCOmed was 25.7 mm (±4.6), mean PCOlat was 23.6 mm (±3.0), mean LMC was 63.7 mm (±5.0) and mean LLC was 64.4 mm (±5.0). Except for PCOmed, the mean values of all other FCM parameters were significantly higher in male knees compared to female knees. ACOmed and PCOmed showed significant side-specific differences. There were no significant differences in relation to age and osteoarthritis. CONCLUSION: The study showed significant differences in FCM side- and gender-specifically in adult knees. These aspects should be considered in the discussion of individual and gender-specific knee joint replacement.

20α-Hydroxysteroid Dehydrogenase Expression in the Human Myometrium at Term and Preterm Birth: Relationships to Fetal Sex and Maternal Body Mass Index.

The mechanism by which human labor is initiated in the presence of elevated circulating progesterone levels remains unknown. Recent evidence indicates that the progesterone-metabolizing enzyme, 20α-hydroxysteroid dehydrogenase (20α-HSD), encoded by the gene AKR1C1, may contribute to functional progesterone withdrawal. We found that AKR1C1 expression significantly increased with labor onset in term myometrium, but not in preterm myometrium. Among preterm laboring deliveries, clinically diagnosed chorioamnionitis was associated with significantly elevated AKR1C1 expression. AKR1C1 expression positively correlated with BMI before labor and negatively correlated with BMI during labor. Analysis by fetal sex showed that AKR1C1 expression was significantly higher in women who delivered male babies compared to women who delivered female babies at term, but not preterm. Further, in pregnancies where the fetus was female, AKR1C1 expression positively correlated with the mother's age and BMI at the time of delivery. In conclusion, the increase in myometrial AKR1C1 expression with term labor is consistent with 20α-HSD playing a role in local progesterone metabolism to promote birth. Interestingly, this role appears to be specific to term pregnancies where the fetus is male. Upregulated AKR1C1 expression in the myometrium at preterm in-labor with clinical chorioamnionitis suggests that increased 20α-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labor. The link between AKR1C1 expression and maternal BMI may provide insight into why maternal obesity is often associated with dysfunctional labor. Higher myometrial AKR1C1 expression in male pregnancies may indicate fetal sex-related differences in the mechanisms that precipitate labor onset at term.

Assessing the Potency of the Novel Tocolytics 2-APB, Glycyl-H-1152, and HC-067047 in Pregnant Human Myometrium.

The intracellular signaling pathways that regulate myometrial contractions can be targeted by drugs for tocolysis. The agents, 2-APB, glycyl-H-1152, and HC-067047, have been identified as inhibitors of uterine contractility and may have tocolytic potential. However, the contraction-blocking potency of these novel tocolytics was yet to be comprehensively assessed and compared to agents that have seen greater scrutiny, such as the phosphodiesterase inhibitors, aminophylline and rolipram, or the clinically used tocolytics, nifedipine and indomethacin. We determined the IC50 concentrations (inhibit 50% of baseline contractility) for 2-APB, glycyl-H-1152, HC-067047, aminophylline, rolipram, nifedipine, and indomethacin against spontaneous ex vivo contractions in pregnant human myometrium, and then compared their tocolytic potency. Myometrial strips obtained from term, not-in-labor women, were treated with cumulative concentrations of the contraction-blocking agents. Comprehensive dose-response curves were generated. The IC50 concentrations were 53 µM for 2-APB, 18.2 µM for glycyl-H-1152, 48 µM for HC-067047, 318.5 µM for aminophylline, 4.3 µM for rolipram, 10 nM for nifedipine, and 59.5 µM for indomethacin. A single treatment with each drug at the determined IC50 concentration was confirmed to reduce contraction performance (AUC) by approximately 50%. Of the three novel tocolytics examined, glycyl-H-1152 was the most potent inhibitor. However, of all the drugs examined, the overall order of contraction-blocking potency in decreasing order was nifedipine > rolipram > glycyl-H-1152 > HC-067047 > 2-APB > indomethacin > aminophylline. These data provide greater insight into the contraction-blocking properties of some novel tocolytics, with glycyl-H-1152, in particular, emerging as a potential novel tocolytic for preventing preterm birth.

Preterm labor with and without chorioamnionitis is associated with activation of myometrial inflammatory networks: a comprehensive transcriptomic analysis.

BACKGROUND: The onset of preterm labor is associated with inflammation. Previous studies suggested that this is distinct from the inflammation observed during term labor. Our previous work on 44 genes differentially expressed in myometria in term labor demonstrated a different pattern of gene expression from that observed in preterm laboring and nonlaboring myometria. We found increased expression of inflammatory genes in preterm labor associated with chorioamnionitis, but in the absence of chorioamnionitis observed no difference in gene expression in preterm myometria regardless of laboring status, suggesting that preterm labor is associated with different myometrial genes or signals originating from outside the myometrium. Given that a small subset of genes were assessed, this study aimed to use RNA sequencing and bioinformatics to assess the myometrial transcriptome during preterm labor in the presence and absence of chorioamnionitis. OBJECTIVE: This study aimed to comprehensively determine protein-coding transcriptomic differences between preterm nonlaboring and preterm laboring myometria with and without chorioamnionitis. STUDY DESIGN: Myometria were collected at cesarean delivery from preterm patients not in labor (n=16) and preterm patients in labor with chorioamnionitis (n=8) or without chorioamnionitis (n=6). Extracted RNA from myometrial tissue was prepared and sequenced using Illumina NovaSeq. Gene expression was quantified by mapping the sequence reads to the human reference genome (hg38). Differential gene expression analysis, gene set enrichment analysis, and weighted gene coexpression network analysis were used to comprehensively interrogate transcriptomic differences and their associated biology. RESULTS: Differential gene expression analysis comparing preterm patients in labor with chorioamnionitis with preterm patients not in labor identified 931 differentially expressed genes, whereas comparing preterm patients in labor without chorioamnionitis with preterm patients not in labor identified no statistically significant gene expression changes. In contrast, gene set enrichment analysis and weighted gene coexpression network analysis demonstrated that preterm labor with and without chorioamnionitis was associated with enrichment of pathways involved in activation of the innate immune system and inflammation, and activation of G protein-coupled receptors. Key genes identified included chemotactic CYP4F3, CXCL8, DOCK2, and IRF1 in preterm labor with chorioamnionitis and CYP4F3, FCAR, CHUK, and IL13RA2 in preterm labor without chorioamnionitis. There was marked overlap in the pathways enriched in both preterm labor subtypes. CONCLUSION: Differential gene expression analysis demonstrated that myometria from preterm patients in labor without chorioamnionitis and preterm patients not in labor were transcriptionally similar, whereas the presence of chorioamnionitis was associated with marked gene changes. In contrast, comprehensive bioinformatic analysis indicated that preterm labor with or without chorioamnionitis was associated with innate immune activation. All causes of preterm labor were associated with activation of the innate immune system, but this was more marked in the presence of chorioamnionitis. These data suggest that anti-inflammatory therapy may be relevant in managing preterm labor of all etiologies.

Unplanned 30-Day Readmissions after Management of Submassive and Massive Acute Pulmonary Embolism: Catheter-Directed versus Systemic Thrombolysis.

PURPOSE: To compare 30-day readmission and in-hospital outcomes from the Nationwide Readmissions Database (NRD) for catheter-directed thrombolysis (CDT) versus systemic intravenous thrombolysis (IVT) as treatments for acute submassive or massive pulmonary embolism (PE). MATERIALS AND METHODS: The NRD was queried from 2016 to 2019 for adult patients with nonseptic acute PE who underwent IVT or CDT. Massive PE was distinguished from submassive PE if patients had concurrent International Classification of Diseases (ICD-10) codes corresponding to mechanical ventilation, vasopressors, or shock. Propensity score-matched analysis was conducted to infer the association of CDT versus IVT in unplanned 30-day readmissions, nonroutine discharge, gastrointestinal bleeding (GIB), and intracranial hemorrhage (ICH). These results are demonstrated as average treatment effects (ATEs) of IVT compared with those of CDT. RESULTS: A total of 37,116 patients with acute PE were studied; 18,702 (50.3%) underwent CDT, and 18,414 (49.7%) underwent IVT. A total of 2,083 (11.1%) and 3,423 (18.6%) were massive PEs in the 2 groups, respectively (P < .001). The ATE of IVT was higher than that of CDT regarding unplanned 30-day readmissions (ATE, 0.019; P < .001), GIB (ATE, 0.012; P < .001), ICH (ATE, 0.003; P = .017), and nonroutine discharge (ATE, 0.022; P = .006). The subgroup analysis of patients with submassive PE demonstrated that IVT had a higher ATE regarding unplanned 30-day readmission (ATE, 0.028; P < .001), GIB (ATE, 0.008; P = .003), ICH (ATE, 0.002; P = .035), and nonroutine discharge (ATE, 0.019; P = .022) than CDT. CONCLUSIONS: CDT had a lower likelihood of unplanned 30-day readmissions, including when stratified by a submassive PE subtype. Additionally, adverse events, including ICH and GIB, were more likely among patients who received IVT than among those who received CDT.