CT in musculoskeletal imaging: still helpful and for what?

Computed tomography (CT) is a common modality employed for musculoskeletal imaging. Conventional CT techniques are useful for the assessment of trauma in detection, characterization and surgical planning of complex fractures. CT arthrography can depict internal derangement lesions and impact medical decision making of orthopedic providers. In oncology, CT can have a role in the characterization of bone tumors and may elucidate soft tissue mineralization patterns. Several advances in CT technology have led to a variety of acquisition techniques with distinct clinical applications. These include four-dimensional CT, which allows examination of joints during motion; cone-beam CT, which allows examination during physiological weight-bearing conditions; dual-energy CT, which allows material decomposition useful in musculoskeletal deposition disorders (e.g., gout) and bone marrow edema detection; and photon-counting CT, which provides increased spatial resolution, decreased radiation, and material decomposition compared to standard multi-detector CT systems due to its ability to directly translate X-ray photon energies into electrical signals. Advanced acquisition techniques provide higher spatial resolution scans capable of enhanced bony microarchitecture and bone mineral density assessment. Together, these CT acquisition techniques will continue to play a substantial role in the practices of orthopedics, rheumatology, metabolic bone, oncology, and interventional radiology.

Is there a need for fresh frozen plasma and platelet transfusion in trauma patients receiving submassive transfusion?

Background: Blood transfusions have become a vital intervention in trauma care. There are limited data on the safety and effectiveness of submassive transfusion (SMT), that is defined as receiving less than 10 units packed red blood cells (PRBCs) in the first 24 hours. This study aimed to evaluate the efficacy and safety of fresh frozen plasma (FFP) and platelet transfusions in patients undergoing SMT. Methods: This is a retrospective cohort, reviewing the Trauma Quality Improvement Program database spanning 3 years (2016 to 2018). Adult patients aged 18 years and older who had received at least 1 unit of PRBC within 24 hours were included in the study. We used a multivariate regression model to analyze the cut-off units of combined resuscitation (CR) (which included PRBCs along with at least one unit of FFP and/or platelets) that leads to survival improvement. Patients were then stratified into two groups: those who received PRBC alone and those who received CR. Propensity score matching was performed in a 1:1 ratio. Results: The study included 85 234 patients. Based on the multivariate regression model, transfusion of more than 3 units of PRBC with at least 1 unit of FFP and/or platelets demonstrated improved mortality compared with PRBC alone. Among 66 319 patients requiring SMT and >3 units of PRBCs, 25 978 received PRBC alone, and 40 341 received CR. After propensity matching, 4215 patients were included in each group. Patients administered CR had a lower rate of complications (15% vs 26%), acute respiratory distress syndrome (3% vs 5%) and acute kidney injury (8% vs 11%). Rates of sepsis and venous thromboembolism were similar between the two groups. Multivariate regression analysis indicated that patients receiving 4 to 7 units of PRBC alone had significantly higher ORs for mortality than those receiving CR. Conclusion: Trauma patients requiring more than 3 units of PRBCs who received CR with FFP and platelets experienced improved survival and reduced complications. Level of evidence: Level III retrospective study.

Modeling primitive and definitive erythropoiesis with induced pluripotent stem cells.

ABSTRACT: During development, erythroid cells are produced through at least 2 distinct hematopoietic waves (primitive and definitive), generating erythroblasts with different functional characteristics. Human induced pluripotent stem cells (iPSCs) can be used as a model platform to study the development of red blood cells (RBCs) with many of the differentiation protocols after the primitive wave of hematopoiesis. Recent advances have established that definitive hematopoietic progenitors can be generated from iPSCs, creating a unique situation for comparing primitive and definitive erythrocytes derived from cell sources of identical genetic background. We generated iPSCs from healthy fetal liver (FL) cells and produced isogenic primitive or definitive RBCs which were compared directly to the FL-derived RBCs. Functional assays confirmed differences between the 2 programs, with primitive RBCs showing a reduced proliferation potential, larger cell size, lack of Duffy RBC antigen expression, and higher expression of embryonic globins. Transcriptome profiling by scRNA-seq demonstrated high similarity between FL- and iPSC-derived definitive RBCs along with very different gene expression and regulatory network patterns for primitive RBCs. In addition, iPSC lines harboring a known pathogenic mutation in the erythroid master regulator KLF1 demonstrated phenotypic changes specific to definitive RBCs. Our studies provide new insights into differences between primitive and definitive erythropoiesis and highlight the importance of ontology when using iPSCs to model genetic hematologic diseases. Beyond disease modeling, the similarity between FL- and iPSC-derived definitive RBCs expands potential applications of definitive RBCs for diagnostic and transfusion products.

CT-derived pectoralis composition and incident pneumonia hospitalization using fully automated deep-learning algorithm: multi-ethnic study of atherosclerosis.

BACKGROUND: Pneumonia-related hospitalization may be associated with advanced skeletal muscle loss due to aging (i.e., sarcopenia) or chronic illnesses (i.e., cachexia). Early detection of muscle loss may now be feasible using deep-learning algorithms applied on conventional chest CT. OBJECTIVES: To implement a fully automated deep-learning algorithm for pectoralis muscle measures from conventional chest CT and investigate longitudinal associations between these measures and incident pneumonia hospitalization according to Chronic Obstructive Pulmonary Disease (COPD) status. MATERIALS AND METHODS: This analysis from the Multi-Ethnic Study of Atherosclerosis included participants with available chest CT examinations between 2010 and 2012. We implemented pectoralis muscle composition measures from a fully automated deep-learning algorithm (Mask R-CNN, built on the Faster Region Proposal Network (R-) Convolutional Neural Network (CNN) with an extension for mask identification) for two-dimensional segmentation. Associations between CT-derived measures and incident pneumonia hospitalizations were evaluated using Cox proportional hazards models adjusted for multiple confounders which include but are not limited to age, sex, race, smoking, BMI, physical activity, and forced-expiratory-volume-at-1 s-to-functional-vital-capacity ratio. Stratification analyses were conducted based on baseline COPD status. RESULTS: This study included 2595 participants (51% female; median age: 68 (IQR: 61, 76)) CT examinations for whom we implemented deep learning-derived measures for longitudinal analyses. Eighty-six incident pneumonia hospitalizations occurred during a median 6.67-year follow-up. Overall, pectoralis muscle composition measures did not predict incident pneumonia. However, in fully-adjusted models, only among participants with COPD (N = 507), CT measures like extramyocellular fat index (hazard ratio: 1.98, 95% CI: 1.22, 3.21, p value: 0.02), were independently associated with incident pneumonia. CONCLUSION: Reliable deep learning-derived pectoralis muscle measures could predict incident pneumonia hospitalization only among participants with known COPD. CLINICAL RELEVANCE STATEMENT: Pectoralis muscle measures obtainable at zero additional cost or radiation exposure from any chest CT may have independent predictive value for clinical outcomes in chronic obstructive pulmonary disease patients. KEY POINTS: •Identification of independent and modifiable risk factors of pneumonia can have important clinical impact on patients with chronic obstructive pulmonary disease. •Opportunistic CT measures of adipose tissue within pectoralis muscles using deep-learning algorithms can be quickly obtainable at zero additional cost or radiation exposure. •Deep learning-derived pectoralis muscle measurements of intermuscular fat and its subcomponents are independently associated with subsequent incident pneumonia hospitalization.

Predictive Value of Deep Learning-derived CT Pectoralis Muscle and Adipose Measurements for Incident Heart Failure: Multi-Ethnic Study of Atherosclerosis.

Purpose: To develop a deep learning algorithm capable of extracting pectoralis muscle and adipose measurements and to longitudinally investigate associations between these measurements and incident heart failure (HF) in participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Materials and Methods: MESA is a prospective study of subclinical cardiovascular disease characteristics and risk factors for progression to clinically overt disease approved by institutional review boards of six participating centers (ClinicalTrials.gov identifier: NCT00005487). All participants with adequate imaging and clinical data from the fifth examination of MESA were included in this study. Hence, in this secondary analysis, manual segmentations of 600 chest CT examinations (between the years 2010 and 2012) were used to train and validate a convolutional neural network, which subsequently extracted pectoralis muscle and adipose (intermuscular adipose tissue (IMAT), perimuscular adipose tissue (PAT), extramyocellular lipids and subcutaneous adipose tissue) area measurements from 3031 CT examinations using individualized thresholds for adipose segmentation. Next, 1781 participants without baseline HF were longitudinally investigated for associations between baseline pectoralis muscle and adipose measurements and incident HF using crude and adjusted Cox proportional hazards models. The full models were adjusted for variables in categories of demographic (age, race, sex, income), clinical/laboratory (including physical activity, BMI, and smoking), CT (coronary artery calcium score), and cardiac MRI (left ventricular ejection fraction and mass (% of predicted)) data. Results: In 1781 participants (median age, 68 (IQR,61, 75) years; 907 [51%] females), 41 incident HF events occurred over a median 6.5-year follow-up. IMAT predicted incident HF in unadjusted (hazard ratio [HR]:1.14; 95% CI: 1.03-1.26) and fully adjusted (HR:1.16, 95% CI: 1.03-1.31) models. PAT also predicted incident HF in crude (HR:1.19; 95% CI: 1.06-1.35) and fully adjusted (HR:1.25; 95% CI: 1.07-1.46) models. Conclusion: The study demonstrates that fast and reliable deep learning-derived pectoralis muscle and adipose measurements are obtainable from conventional chest CT, which may be predictive of incident HF.©RSNA, 2023.

Direct Peritoneal Resuscitation (DPR) Improves Acute Physiology and Chronic Health Evaluation (APACHE) IV and Acute Physiology Score When Used in Damage Control Laparotomies: Prospective Cohort Study on 37 Patients.

INTRODUCTION: Using direct peritoneal resuscitation (DPR) as an adjunct when managing patients undergoing damage control laparotomy (DCL) shows promising results. We report our initial experience in utilizing DPR when managing patients who underwent DCL for emergent surgery at the index operation. MATERIALS AND METHODS: We prospectively collected data on 37 patients between August 2020 to October 2021 who underwent DCL with open abdomens after the index operation and utilized DPR. DPR was performed using peritoneal lavage with DIANEAL PD-2-D 2.5% Ca 3.5 mEq/L at a rate of 400ml/hour. Patients' physiological scores and clinical outcomes were evaluated. RESULTS: 86% required DCL and DPR due to septic abdomen/bowel ischemia. The median (interquartile range [IQR]) age was 62 years (53-70); 62% were male, and median (IQR) body mass index was 30.0kg/m2 (25.5-38.4). On DPR initiation, median (IQR) APACHE-IV score was 48 (33-64) and median (IQR) Acute Physiology Score (APS) was 31 (18-54). After initiation, median (IQR) APACHE-IV score and median (IQR) APS were 39 (21-62) and 19 (11-56), respectively, and both showed significant improvement in survivors (p<0.05). Median (IQR) DPR duration was four days (2-8) and primary abdominal closure was achieved in 30 patients (81%). There were eight mortalities (21.6%) within 30 days postoperatively, of which seven were within 3-24 days due to uncontrolled sepsis/multiple organ failure. The most frequent complication was surgical-site infection recorded in 12 patients (32%). Twenty-four patients (67%) were discharged home/transferred to a rehab center/nursing home. CONCLUSION: DPR application showed significant improvement of APACHE-IV score and APS in patients with peritonitis/septic abdomen.

Serial rotational thromboelastography (ROTEM) in mechanically ventilated patients with COVID-19 demonstrates hypercoagulopathy despite therapeutic heparinization.

Background: Clinical hypercoagulopathy in patients with COVID-19 has been anecdotally described, but there is lack of evidence due to the novelty of this disease. Our study reports the results of rotational thromboelastography (ROTEM) in relation to traditional laboratory coagulation tests and acute phase markers among a cohort of severely ill, mechanically ventilated patients with COVID-19. Methods: Patients with COVID-19 (N=21) with respiratory failure requiring mechanical ventilation were included in this prospective case series. ROTEM was serially obtained for all patients on three different days during their intensive care unit (ICU) stay and analyzed using repeated measures analysis. Demographic variables, symptoms at the time of presentation, ROTEM values, laboratory values for traditionally measured coagulation profiles, and acute phase reactants were analyzed, in addition to the use of anticoagulation and clinical hypercoagulopathic complications. Results: The average age of our cohort was 57.9 years old (SD=14.4) and 76.2% were male. The mortality rate was 14.3% (3 of 21). Two patients (12.5%) were identified to have new-onset deep vein thrombosis, two patients (12.5%) were found to have ≥3 episodes of central venous catheter thrombosis, and three patients (18.7%) had confirmed stroke. ROTEM demonstrated elevated EXTEM and INTEM clotting times, including elevated FIBTEM maximum clot firmness (MCFFIB). All patients treated with therapeutic anticoagulation still demonstrated hypercoagulopathy within the MCFFIB tests. Discussion: Repeated measure ROTEMs were able to detect hypercoagulopathy in ICU patients with COVID-19 despite therapeutic anticoagulation with heparin. Level of evidence: III.

Firearms: the leading cause of years of potential life lost.

OBJECTIVES: Data from the Centers for Disease Control and Prevention (CDC) show that firearm deaths are increasing in the USA. The aims of this study were to determine the magnitude of potential years of life lost due to firearms and to examine the evolution of firearm deaths on the basis of sex, race, and geographical location within the USA. METHODS: Data was extracted (2009-2018) from the National Vital Statistics Reports from the CDC and the Web-based Injury Statistics Query and Reporting System database. Years of potential life lost was calculated by the CDC standard of subtracting the age at death from the standard year of 80, and then summing the individual years of potential life lost (YPLL) across each cause of death. RESULTS: The YPLL in 2017 and 2018 was higher for firearms than motor vehicle crashes (MVCs). In 2018, the YPLL for firearms was 1.42 million and 1.34 million for MVC. Males comprised the majority (85.4%) of the 38 929 firearm deaths. White males had the most YPLL due to suicide, with 4.95 million YPLL during the course of the 10-year period; black males had the most YPLL due to homicide with 3.2 million YPLL during the same time period. The largest number of suicides by firearms was in older white males. Firearm-related injury deaths were highest in the South, followed by the West, Midwest, and Northeast, respectively. CONCLUSION: Firearms are now the leading cause of YPLL in trauma. Firearm deaths have overtaken MVC as the mechanism for the main cause of potential years of life lost since 2017. Suicide in white males accounts for more YPLL than homicides. Deaths related to firearms are potentially preventable causes of death and prevention efforts should be redirected. LEVEL OF EVIDENCE: Level III-Descriptive Study.

Cortical and Subcortical Dysmetabolism Are Dynamic Markers of Clinical Disability and Course in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: This [18F]fluorodeoxyglucose (FDG) PET study evaluates the accuracy of semiquantitative measurement of putaminal hypermetabolism in identifying anti-leucine-rich, glioma-inactivated-1 (LGI1) protein autoimmune encephalitis (AE). In addition, the extent of brain dysmetabolism, their association with clinical outcomes, and longitudinal metabolic changes after immunotherapy in LGI1-AE are examined. METHODS: FDG-PET scans from 49 age-matched and sex-matched subjects (13 in LGI1-AE group, 15 in non-LGI1-AE group, 11 with Alzheimer disease [AD], and 10 negative controls [NCs]) and follow-up scans from 8 patients with LGI1 AE on a median 6 months after immunotherapy were analyzed. Putaminal standardized uptake value ratios (SUVRs) normalized to global brain (P-SUVRg), thalamus (P/Th), and midbrain (P/Mi) were evaluated for diagnostic accuracy. SUVRg was applied for all other analyses. RESULTS: P-SUVRg, P/Th, and P/Mi were higher in LGI1-AE group than in non-LGI1-AE group, AD group, and NCs (all p < 0.05). P/Mi and P-SUVRg differentiated LGI1-AE group robustly from other groups (areas under the curve 0.84-0.99). Mediotemporal lobe (MTL) SUVRg was increased in both LGI1-AE and non-LGI1-AE groups when compared with NCs (both p < 0.05). SUVRg was decreased in several frontoparietal regions and increased in pallidum, caudate, pons, olfactory, and inferior occipital gyrus in LGI1-AE group when compared with that in NCs (all p < 0.05). In LGI1-AE group, both MTL and putaminal hypermetabolism were reduced after immunotherapy. Normalization of regional cortical dysmetabolism associated with clinical improvement at the 6- and 20-month follow-up. DISCUSSION: Semiquantitative measurement of putaminal hypermetabolism with FDG-PET may be used to distinguish LGI1-AE from other pathologies. Metabolic abnormalities in LGI1-AE extend beyond putamen and MTL into other subcortical and cortical regions. FDG-PET may be used in evaluating disease evolution in LGI1-AE. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that semiquantitative measures of putaminal metabolism on PET can differentiate patients with LGI1-AE from patients without LGI1-AE, patients with AD, or NCs.

Neurologic Complications of Surgery and Anesthesia.

Surgery and anesthesia carry risks of ischemic, hemorrhagic, hypoxic, and metabolic complications, all of which can result in neurologic symptoms and deficits. Patients with underlying cardiovascular and cerebrovascular risk factors are particularly vulnerable. In this article the authors review the neurologic complications of surgery and anesthesia, with a focus on the role of the neurologic consultant in preoperative evaluation and risk stratification and diagnosis and management of postoperative complications.

Modular fluorescent nanoparticle DNA probes for detection of peptides and proteins.

Fluorescently labeled antibody and aptamer probes are used in biological studies to characterize binding interactions, measure concentrations of analytes, and sort cells. Fluorescent nanoparticle labels offer an excellent alternative to standard fluorescent labeling strategies due to their enhanced brightness, stability and multivalency; however, challenges in functionalization and characterization have impeded their use. This work introduces a straightforward approach for preparation of fluorescent nanoparticle probes using commercially available reagents and common laboratory equipment. Fluorescent polystyrene nanoparticles, Thermo Fisher Scientific FluoSpheres, were used in these proof-of-principle studies. Particle passivation was achieved by covalent attachment of amine-PEG-azide to carboxylated particles, neutralizing the surface charge from - 43 to - 15 mV. A conjugation-annealing handle and DNA aptamer probe were attached to the azide-PEG nanoparticle surface either through reaction of pre-annealed handle and probe or through a stepwise reaction of the nanoparticles with the handle followed by aptamer annealing. Nanoparticles functionalized with DNA aptamers targeting histidine tags and VEGF protein had high affinity (EC50s ranging from 3 to 12 nM) and specificity, and were more stable than conventional labels. This protocol for preparation of nanoparticle probes relies solely on commercially available reagents and common equipment, breaking down the barriers to use nanoparticles in biological experiments.

Influence of Autoimmune Antibody Testing on the Use of Immunotherapy on an Inpatient Neurology Service.

OBJECTIVE: To determine the frequency of autoimmune antibody testing in an inpatient neurology setting and its influence on immunotherapy use on an inpatient neurology service. METHODS: A retrospective descriptive cohort study of patients admitted to the neurology inpatient service at a large tertiary academic medical center who had autoimmune and/or paraneoplastic antibody testing performed between 10/1/2017 and 10/1/2018. Characteristics of patients' initial clinical presentation, antibody testing results, test timing in relation to initiating immunotherapy, and final diagnosis using consensus criteria were extracted and analyzed. Case reports of patients with positive antibody panels are presented. RESULTS: Of 1,604 patients, 50 patients (3.1%) had an antibody panel sent. Tests resulted after an average of 17 days (range 7-27). The most common clinical presenting symptom in those with a panel sent was encephalopathy. There were 5 (10%) positive serum panels and no positive CSF panels. Only one of these 5 patients had autoimmune encephalitis and was treated with immunotherapy. Of those with negative serum and CSF panels, 15 were treated acutely with empiric immunotherapy and the remainder with supportive care. Of those treated with immunotherapy, 14/15 (93%) were treated before the panel tests resulted. Four patients who had negative panels but were empirically treated met consensus criteria for an autoimmune-mediated neurologic process. CONCLUSION: Our study suggests that the results of antibody testing did not influence inpatient neurologists' decision to treat with immunotherapy as most treatments began prior to final results being available.

Study of inherited thrombocytopenia resulting from mutations in ETV6 or RUNX1 using a human pluripotent stem cell model.

Inherited thrombocytopenia results in low platelet counts and increased bleeding. Subsets of these patients have monoallelic germline mutations in ETV6 or RUNX1 and a heightened risk of developing hematologic malignancies. Utilizing CRISPR-Cas9, we compared the in vitro phenotype of hematopoietic progenitor cells and megakaryocytes derived from induced pluripotent stem cell (iPSC) lines harboring mutations in either ETV6 or RUNX1. Both mutant lines display phenotypes consistent with a platelet-bleeding disorder. Surprisingly, these cellular phenotypes were largely distinct. The ETV6-mutant iPSCs yield more hematopoietic progenitor cells and megakaryocytes, but the megakaryocytes are immature and less responsive to agonist stimulation. On the contrary, RUNX1-mutant iPSCs yield fewer hematopoietic progenitor cells and megakaryocytes, but the megakaryocytes are more responsive to agonist stimulation. However, both mutant iPSC lines display defects in proplatelet formation. Our work highlights that, while patients harboring germline ETV6 or RUNX1 mutations have similar clinical phenotypes, the molecular mechanisms may be distinct.

Early versus delayed complex abdominal wall reconstruction with biologic mesh following damage-control surgery.

BACKGROUND: Damage-control surgery for trauma and intra-abdominal catastrophe is associated with a high rate of morbidities and postoperative complications. This study aimed to compare the outcomes of patients undergoing early complex abdominal wall reconstruction (e-CAWR) in acute settings versus those undergoing delayed complex abdominal wall reconstruction (d-CAWR). METHOD: This study was a pooled analysis derived from the retrospective and prospective database between the years 2013 and 2019. The outcomes were compared for differences in demographics, presentation, intraoperative variables, Ventral Hernia Working Grade (VHWG), US Centers for Disease Control and Prevention wound class, American Society of Anesthesiologists (ASA) scores, postoperative complications, hospital length of stay, and readmission rates. We performed Student's t test, χ2 test, and Fisher's exact test to compare variables of interest. Multivariable linear regression model was built to evaluate the association of hospital length of stay and all other variables including the timing of complex abdominal wall reconstruction (CAWR). A p value of <0.05 was considered significant. RESULTS: Of the 236 patients who underwent CAWR with biological mesh, 79 (33.5%) had e-CAWR. There were 45 males (57%) and 34 females (43%) in the e-CAWR group. The ASA scores of IV and V, and VHWG grades III and IV were significantly more frequent in the e-CAWR group compared with the d-CAWR one. Postoperatively, the incidence of surgical site occurrence, Clavien-Dindo complications, comprehensive complication index, unplanned reoperations, and mortality were similar between the two groups. Backward linear regression model showed that the timing of CAWR (ß = -11.29, p < 0.0001), ASA (ß = 3.98, p = 0.006), VHWG classification (ß = 3.62, p = 0.015), drug abuse (ß = 13.47, p = 0.009), and two comorbidities of cirrhosis (ß = 12.34, p = 0.001) and malignancy (ß = 7.91, p = 0.008) were the significant predictors of the hospital length of stay left in the model. CONCLUSION: Early CAWR led to shorter hospital length of stay compared with d-CAWR in multivariable regression model. LEVEL OF EVIDENCE: Therapeutic, level IV.

Firearm Deaths are Increasing and Endemic in the USA: It is a Problem of Suicides and Not Homicides.

BACKGROUND: To analyze and report on the changes in epidemiology traumatic causes of death in the USA. METHODS: Data were extracted from the annual National Vital Statistics Reports (2008-2017) from Center for Disease Control and analyzed for trends during the time period given. Generalized additive model was applied to evaluate the significance of trend using R software. RESULTS: Firearm deaths (39,790) and firearm death rate (12.2/100,000) in 2017 were the highest reported, and this increasing trend was significant (p < 0.001) the last ten years. Deaths from motor vehicle crash (MVC) and firearm homicides did not change significantly during the same time period. Firearm deaths were lower than MVC deaths by 21% (8,197/39,790) in 2008, but after 10 years, the difference was only 1% (458/40,231). Years of life lost from firearms is now higher than MVC. Suicides by firearm in 2017 were the highest reported at 23,854/39,773 (60%). In 2017, suicides by firearm victims were predominantly white 20,328/23,562 (85%), men 20,362/23,562 (86%), and the largest group was between the ages of 55-64. CONCLUSIONS: Death from firearms in the USA is increasing and endemic. They were the highest ever reported in 2017 by the CDC. While deaths from MVC used to be the main cause of traumatic death in the USA, deaths from firearms now almost equal it. Calculated years of life lost from firearms is now more than from MVC. Most firearm deaths are not from homicides but are from suicides, and they are predominantly in white older males of the baby boomer generation (born 1946-1964).

The use of GnRH-agonist trigger for the final maturation of oocytes in normal and low responders undergoing planned oocyte cryopreservation.

STUDY QUESTION: Does GnRH-agonist trigger offer similar maturity rate (MR) in low and normal responders compared to high responders in women undergoing planned oocyte cryopreservation, for whom even a small risk of ovarian hyperstimulation syndrome (OHSS) may not be acceptable? SUMMARY ANSWER: GnRH-agonist is an appropriate choice for final maturation of oocytes in planned oocyte cryopreservation, regardless of response to stimulation or risk of ovarian hyperstimulation syndrome. WHAT IS KNOWN ALREADY: Numerous studies have demonstrated the utility of GnRH-agonist trigger for the prevention of ovarian hyperstimulation in high-responder in vitro fertilization cycles. Limited data exist supporting its use in normal or low responders, or in non-infertile women undergoing planned oocyte cryopreservation. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 1189 subjects including all planned oocyte cryopreservation cycles performed at a large, single center, oocyte cryopreservation program from April 2016 to December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1680 cycles were included in the study. A total of 57.1% (959/1680) utilized GnRH-agonist for trigger. Demographic and clinical data were collected from the medical record. Maturation rate was calculated for the entire cohort, and by trigger type, using the quotient of Metaphase II (MII) oocytes and retrieved oocytes. A sub-cohort of GnRH-agonist trigger cycles were categorized by peak estradiol (E2) levels and maturation rates compared between groups. Associations were made using Student's t test, ANOVA, Mann-Whitney U and Kruskal-Wallis, where appropriate. A sample size calculation for 90% power with a significance of 5% to detect non-inferiority of <0.05 from a 0.75 maturity rate between subjects with E2 > 3000 pg/mL and E2 < 3000 pg/mL demonstrated the need for at least 116 cycles per group. MAIN RESULTS AND THE ROLE OF CHANCE: Mean MR was 0.71 ± 0.19 overall, and 0.73 ± 0.18 in the sub-cohort of GnRH-agonist trigger cycles. A total of 611 cycles (63.7%) had peak E2 < 3000, and 331 (34.5%) had E2 > 3000. No significant difference in maturity rate was noted between cycles with E2 levels >3000 pg/mL and <3000 pg/mL (0.72 ± 0.19 vs. 0.74 ± 0.14, P = 0.18), confirming the non-inferiority of maturity rates with GnRH-agonist triggers in cycles with peak E2 < 3000 pg/mL. While lower mean oocytes retrieved and mean MII oocytes were associated with lower peak E2 levels, maturity rate did not significantly differ amongst E2 level groups. Cycles with E2 < 1000 pg/mL had lower MR irrespective of trigger type. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature cannot entirely exclude selection biases, confounding factors or additional variables that could not be accounted for or were not collected by the electronic medical record. Given the nature of planned oocyte cryopreservation, studies of ongoing pregnancy rates and birth outcomes will naturally be delayed. Lastly, the study population was limited to women undergoing planned oocyte cryopreservation; therefore, the results may not be generalizable to women undergoing in vitro fertilization. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study specifically comparing the efficacy of GnRH-agonist in patients at lower risk for OHSS to those at high risk, as well the first study evaluating GnRH-agonist's efficacy specifically in planned oocyte cryopreservation cycles. STUDY FUNDING/COMPETING INTEREST(S): Study support provided by departmental funds from the Center for Fertility Research and Education-Extend Fertility Medical Practice. BLM discloses personal fees from Ferring Pharmaceuticals and Merck KgAA, unrelated to the submitted work. C.S., M.G., L.R. and J.K. have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Glycomic and Proteomic Changes in Aging Brain Nigrostriatal Pathway.

Parkinson's disease (PD) is a neurological disorder characterized by the progressive loss of functional dopaminergic neurons in the nigrostriatal pathway in the brain. Although current treatments provide only symptomatic relief, gene therapy has the potential to slow or halt the degeneration of nigrostriatal dopamine neurons in PD patients. Adeno-associated viruses (AAV) are vectors of choice in gene therapy because of their well-characterized safety and efficacy profiles; however, although gene therapy has been successful in preclinical models of the disease, clinical trials in humans have failed to demonstrate efficacy. Significantly, all primary AAV receptors of the virus are glycans. We thus hypothesize that age related changes in glycan receptors of heparan sulfate (HS) proteoglycans (receptor for rAAV2), and/or N-glycans with terminal galactose (receptor for rAAV9) results in poor adeno-associated virus binding in either the striatum or substantia nigra, or both, affecting transduction and gene delivery. To test our hypothesis we analyzed the striatum and substantia nigra for changes in HS, N-glycans and proteomic signatures in young versus aged rat brain striatum and substantia nigra. We observed different brain region-specific HS disaccharide profiles in aged compared with young adult rats for brain region-specific profiles in striatum versus substantia nigra. We observed brain region- and age-specific N-glycan compositional profiles with respect to the terminal galactose units that serve as receptors for AAV9. We also observed brain region-specific changes in protein expression in the aging nigrostriatal pathway. These studies provide insight into age- and brain region-specific changes in glycan receptors and proteome that will inform design of improved viral vectors for Parkinson Disease (PD) gene therapy.

Neuroradiologic Pearls for Neuro-oncology.

PURPOSE OF REVIEW: This article reviews key principles in the identification of tumors of the central nervous system (CNS) using standard and advanced imaging modalities. This article highlights the pitfalls and pearls of the imaging evaluation of patients with cancer at time of diagnosis and during cancer therapy and discusses the challenges of the imaging evaluation of treatment-related toxicities. RECENT FINDINGS: Treatment of CNS tumors with surgery, chemotherapy, or radiation alters the imaging appearance of the tumor and can be associated with a variety of treatment-related toxicities. The clinician must be familiar with how to assess response to treatment and how to differentiate tumor progression from treatment-related effects. SUMMARY: Management and follow-up of neuro-oncology patients is optimized by a comprehensive radiologic approach to CNS tumors and recognition of the challenges in the assessment of response to treatments.

Yield of Brain MRI in Clinically Diagnosed Epilepsy in the Kingdom of Bhutan: A Prospective Study.

BACKGROUND: People with epilepsy (PWE) in low- and middle-income countries may not access the health resources that are considered optimal for epilepsy diagnosis. The diagnostic yield of magnetic resonance imaging (MRI) has not been well studied in these settings. OBJECTIVES: To report the diagnostic yield of brain MRI and identify clinical associations of abnormal MRI findings among PWE in a neurocysticercosis-endemic, resource-limited setting and to identify the proportion and putative structural brain causes of drug-resistant epilepsy. METHODS: PWE were prospectively enrolled at the Jigme Dorji Wangchuck National Referral Hospital in Bhutan (2014-2015). Each participant completed clinical questionnaires and a 1.5-Tesla brain MRI. Each MRI was reviewed by at least 1 radiologist and neurologist in Bhutan and the United States. A working definition of drug-resistant epilepsy for resource-limited settings was given as (a) seizures for >1 year, (b) at least 1 seizure in the prior year, and (c) presently taking 2 or more antiepileptic drugs (AEDs). Logistic regression models were constructed to test the cross-sectional association of an abnormal brain MRI with clinical variables. FINDINGS: A total of 217 participants (125 [57%] female; 54 [25%] < 18 years old; 199 [92%] taking AEDs; 154 [71%] with a seizure in the prior year) were enrolled. There was a high prevalence of abnormal brain MRIs (176/217, 81%). Mesial temporal sclerosis was the most common finding (n = 115, 53%, including 24 children), exceeding the number of PWE with neurocysticercosis (n = 26, 12%, including 1 child) and congenital/perinatal abnormalities (n = 29, 14%, including 14 children). The number of AEDs (odds ratio = .59, P = .03) and duration of epilepsy (odds ratio = 1.11, P = .02) were significantly associated with an abnormal MRI. Seizure in the prior month was associated with the presence of mesial temporal sclerosis (odds ratio = .47, P = .01). A total of 25 (12%) participants met our definition of drug-resistant epilepsy, with mesial temporal sclerosis (n = 10), congenital malformations (n = 5), and neurocysticercosis (n = 4) being the more common findings. CONCLUSIONS: The prevalence of abnormalities on brain MRI for PWE in resource-limited settings is high as a result of a diffuse range of etiologies, most commonly mesial temporal sclerosis. Drug-resistant epilepsy accounted for 12% of the referral population in a conservative estimation.