National trends in perioperative epidural analgesia use for surgical patients.

STUDY OBJECTIVE: Newer regional anesthesia techniques and minimally invasive surgeries have yielded decreased postoperative pain scores, potentially leading to decreased need for perioperative epidural analgesia. Limited literature is available on trends in usage rates of epidurals. The objective of this study was to identify trends in perioperative epidural analgesia rates among multiple fields of surgery. METHODS: All patients undergoing general, thoracic, urologic, plastic, vascular, orthopedic, or gynecological surgery in 2014-2020 were included from the National Surgical Quality Improvement Program database of over 700 hospitals in the U.S. and 11 different countries. Annual trends in epidural analgesia for all surgeries and each surgical specialty were assessed by mixed effects multivariable logistic regression. The odds ratios (OR) and 99 % confidence intervals (CI) were reported. RESULTS: There were 3,111,435 patients from 2014 to 2020 that were included in the final analysis, in which 107,209 (3.4 %) received perioperative epidural analgesia. Among all surgeries combined, epidural use throughout the study period decreased (OR 0.98 per year, 99 % CI 0.97-0.98, P < 0.001). When only analyzing the surgeries with the top 5 most frequent epidural use per specialty, there was no statistically significant trend in epidural utilization (OR 0.99 per year, 99 % CI 0.99-1.00, P = 0.09). However, there was an increasing trend in epidural utilization in general surgery (OR 1.05 per year, 99 % CI 1.03-1.07, P < 0.001) and vascular surgery (OR 1.08 per year, 99 % CI 1.05-1.10, P < 0.001). CONCLUSION: Rates of perioperative epidural analgesia use has decreased in recent years overall, however, among surgeries within the general surgery and vascular surgery specialty, utilization has increased for procedures that have the highest rates of usage.

On the development and validation of large language model-based classifiers for identifying social determinants of health.

The assessment of social determinants of health (SDoH) within healthcare systems is crucial for comprehensive patient care and addressing health disparities. Current challenges arise from the limited inclusion of structured SDoH information within electronic health record (EHR) systems, often due to the lack of standardized diagnosis codes. This study delves into the transformative potential of large language models (LLM) to overcome these challenges. LLM-based classifiers-using Bidirectional Encoder Representations from Transformers (BERT) and A Robustly Optimized BERT Pretraining Approach (RoBERTa)-were developed for SDoH concepts, including homelessness, food insecurity, and domestic violence, using synthetic training datasets generated by generative pre-trained transformers combined with authentic clinical notes. Models were then validated on separate datasets: Medical Information Mart for Intensive Care-III and our institutional EHR data. When training the model with a combination of synthetic and authentic notes, validation on our institutional dataset yielded an area under the receiver operating characteristics curve of 0.78 for detecting homelessness, 0.72 for detecting food insecurity, and 0.83 for detecting domestic violence. This study underscores the potential of LLMs in extracting SDoH information from clinical text. Automated detection of SDoH may be instrumental for healthcare providers in identifying at-risk patients, guiding targeted interventions, and contributing to population health initiatives aimed at mitigating disparities.

Prenatal Phenotype of Alkuraya-Kucinskas Syndrome: A Novel Case and Systematic Literature Review.

Alkuraya-Kucinskas syndrome (AKS) is an autosomal recessive multisystem disorder resulting from mutations in the BLTP1 gene, formerly known as KIAA1109. Primary manifestations include brain malformations, arthrogryposis, and clubfeet. Cardiac, renal, and ophthalmologic abnormalities may also be observed, while nonimmune hydrops is rare. We present a case of two novel BLTP1 canonical splice-site variants in a fetus with multiple congenital anomalies, including hydrops, a kinked brainstem, and joint contractures. A systematic literature review was conducted to describe the prenatal phenotype of AKS, which was inspired by our case. Our systematic literature review of the prenatal phenotype in 19 cases, including our additional case, demonstrated joint contractures in 90% (18/20), ventriculomegaly in 60% (12/20), brainstem dysgenesis in 50% (10/20), cerebellar hypoplasia in 50% (10/20), parenchymal thinning with lissencephalic aspect in 60% (12/20), and facial dysmorphism in 70% (14/20) of reported AKS cases. In addition to our case, hydrops was reported in two other families. AKS should be considered in fetal presentations with characteristic features, especially brainstem kinking and joint contractures. Exome sequencing, including coverage of canonical intronic splice-site variants, can clarify the diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT03911531.

Classifying High-Risk Patients for Persistent Opioid Use After Major Spine Surgery: A Machine-Learning Approach.

BACKGROUND: Persistent opioid use is a common occurrence after surgery and prolonged exposure to opioids may result in escalation and dependence. The objective of this study was to develop machine-learning-based predictive models for persistent opioid use after major spine surgery. METHODS: Five classification models were evaluated to predict persistent opioid use: logistic regression, random forest, neural network, balanced random forest, and balanced bagging. Synthetic Minority Oversampling Technique was used to improve class balance. The primary outcome was persistent opioid use, defined as patient reporting to use opioids after 3 months postoperatively. The data were split into a training and test set. Performance metrics were evaluated on the test set and included the F1 score and the area under the receiver operating characteristics curve (AUC). Feature importance was ranked based on SHapley Additive exPlanations (SHAP). RESULTS: After exclusion (patients with missing follow-up data), 2611 patients were included in the analysis, of which 1209 (46.3%) continued to use opioids 3 months after surgery. The balanced random forest classifiers had the highest AUC (0.877, 95% confidence interval [CI], 0.834-0.894) compared to neural networks (0.729, 95% CI, 0.672-0.787), logistic regression (0.709, 95% CI, 0.652-0.767), balanced bagging classifier (0.859, 95% CI, 0.814-0.905), and random forest classifier (0.855, 95% CI, 0.813-0.897). The balanced random forest classifier had the highest F1 (0.758, 95% CI, 0.677-0.839). Furthermore, the specificity, sensitivity, precision, and accuracy were 0.883, 0.700, 0.836, and 0.780, respectively. The features based on SHAP analysis with the highest impact on model performance were age, preoperative opioid use, preoperative pain scores, and body mass index. CONCLUSIONS: The balanced random forest classifier was found to be the most effective model for identifying persistent opioid use after spine surgery.

GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade.

During Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by binding the protein kinase A catalytic subunit (PKA-C) and physically blocking its enzymatic activity. Here, we show that GPCR kinase 2 (GRK2) orchestrates this process during endogenous mouse and zebrafish Hh pathway activation in the primary cilium. Upon SMO activation, GRK2 rapidly relocalizes from the ciliary base to the shaft, triggering SMO phosphorylation and PKA-C interaction. Reconstitution studies reveal that GRK2 phosphorylation enables active SMO to bind PKA-C directly. Lastly, the SMO-GRK2-PKA pathway underlies Hh signal transduction in a range of cellular and in vivo models. Thus, GRK2 phosphorylation of ciliary SMO and the ensuing PKA-C binding and inactivation are critical initiating events for the intracellular steps in Hh signaling. More broadly, our study suggests an expanded role for GRKs in enabling direct GPCR interactions with diverse intracellular effectors.

Recombinant erythropoietin for the treatment of iron deficiency anemia in pregnancy: A systematic review.

BACKGROUND: Treatment options for severe, refractory iron deficiency anemia are limited in pregnancy. OBJECTIVE: To review the available literature on the use of recombinant erythropoietin in the treatment of iron deficiency anemia in pregnancy. SEARCH STRATEGY: An electronic search of seven databases from inception to March 2022 was performed using a combination of keywords. SELECTION CRITERIA: We included all randomized controlled or observational studies of pregnant patients with iron deficiency anemia who received recombinant erythropoietin or control. The primary outcome was a change in hematologic parameters (hemoglobin or hematocrit) after treatment. Studies were appraised using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. DATA COLLECTION AND ANALYSIS: Data were summarized using narrative synthesis and descriptive statistics as appropriate. This study was registered with PROSPERO, CRD42022313328. MAIN RESULTS: Of 234 studies screened, five studies met the inclusion criteria and had sufficient data for analysis (n = 103 recombinant erythropoietin and n = 104 controls). All patients in the intervention group received iron supplementation (intravenous or oral) in addition to recombinant erythropoietin. All patients in the control group received iron supplementation (intravenous or oral) alone. As the result of variance between studies in inclusion criteria, the timing of repeat blood draws, and data reporting, a meta-analysis could not be performed. Three studies found that serial recombinant erythropoietin combined with iron supplementation was more effective at raising hematologic laboratory parameters (hemoglobin or hematocrit) than iron alone. One study reported no difference in hemoglobin or hematocrit levels between groups at day 28. However, patients in this study only received one dose of recombinant erythropoietin, whereas those in the other studies received serial doses. Another study also found no difference in hemoglobin levels by day 28, but patients in the recombinant erythropoietin group had lower hemoglobin levels at baseline and a more rapid rise in hemoglobin than iron alone. This is demonstrated by a more significant rise in hemoglobin at day 11 in the recombinant erythropoietin group than in the control group. CONCLUSIONS: Serial recombinant erythropoietin administration and iron supplementation may be more effective at treating refractory iron deficiency anemia in pregnancy than iron supplementation alone.

Propranolol to decrease time to delivery: a meta-analysis of randomized controlled trials.

OBJECTIVE: To assess the effect of propranolol on time to delivery among patients undergoing induction or augmentation of labor. DATA SOURCES: PubMed, Scopus, Cochrane Library, ClinicalTrials.gov, and CINAHL (EBSCO) were searched from inception to December 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials (RCTs) that examined the impact of propranolol on time to delivery among patients undergoing induction or augmentation of labor were included. RCTs that included stillbirth before randomization, non-randomized trials, observational, cohort, case control, or studies in which the control group included an intervention other than standard care were excluded. STUDY APPRAISAL AND SYNTHESIS METHODS: Primary outcome was time to delivery after administration of propranolol among patients undergoing induction or augmentation of labor. The summary measures were reported as summary mean difference (MD) or relative risk with 95% confidence interval (CI). RESULTS: Nine RCTs including 1,182 patients were included in this meta-analysis. Five studies investigated the effect of propranolol among patients undergoing induction of labor (IOL) and demonstrated a significant decrease in time to delivery (MD, -91.5 minutes, 95% CI -110.6 to -72.4). Four studies investigated the effect of propranolol among patients undergoing augmentation of labor and showed no significant decrease in time to delivery (MD, -2.98 minutes, 95% CI -21.6 to 15.6). Our pooled analysis demonstrated that the use of propranolol in IOL and augmentation was associated with a decrease in time to delivery from administration of propranolol compared to placebo (mean difference, -46.15 minutes, 95% CI -59.48 to -32.81). The meta-analysis found no increased risk of PPH, blood transfusion, cesarean delivery rates, or NICU admission with the use of propranolol during labor. CONCLUSION: The use of propranolol during induction of labor shortens overall time to delivery by about 91 minutes and did not significantly decrease time to delivery in those undergoing augmentation of labor.

Reliability of cervicocephalic sense of force.

Cervicocephalic proprioception (CCP) is an important assessment item for people with a range of clinical conditions, where reduced CCP is associated with neck pain and imbalance. Reliability has been established for a range of positional and movements tests, but there is limited data regarding sense of force, particularly across three planes of movement. The current test-retest study assessed reliability when evaluating sense of force in healthy adults (8 males, 6 females, mean age 31.50 years [SD 10.14]) over two sessions, 4-7 days apart. A force matching protocol was used to evaluate reliability of absolute error (AE), constant error (CE), and variable error (VE) for 10 % and 25 % maximal voluntary contraction (MVC) target forces for flexion, extension, lateral flexion, and rotation. Participants were strapped to a chair to limit trunk movement and data was captured using a compressive force transducer fixed to an adjustable wall mount. Six trials were performed for each contraction-type, totaling 72 submaximal MVCs per session. ICC estimates for AE (0.15-0.77), CE (0.01-0.85), and VE (0.00-0.83) were varied and confidence intervals were mostly wide. Considering lower limits of confidence intervals, CE had best reliability values generally, but more specifically the most reliable contraction type and movement was 25 % MVC flexion (ICC 0.85, confidence interval 0.54-0.95). This study found that reliability for sense of force testing was dependent upon contraction, type of error, and target force utilized. Further reliability analysis should be performed when applying this test to measure validity outcomes in clinical populations.

Paravertebral versus Pectoralis-II (Interpectoral and Pectoserratus) Nerve Blocks for Postoperative Analgesia after Non-Mastectomy Breast Surgery: A Randomized, Controlled, Observer-Masked Noninferiority Trial.

BACKGROUND: Pectoralis-II and paravertebral nerve blocks are both used to treat pain following breast surgery. Most previous studies involving mastectomy identified little difference of significance between the two approaches. Whether this is also accurate for non-mastectomy procedures remains unknown. METHODS: Participants undergoing uni- or bilateral non-mastectomy breast surgery anticipated to have at least moderate postoperative pain were randomized to a pectoralis-II or paravertebral block (90 mg ropivacaine/side for both). Surgeons and recovery room staff were masked to treatment group assignment, and participants were not informed of their treatment group. Injectate for pectoralis-II blocks was ropivacaine 0.3% (30 mL) per side. Injectate for paravertebral blocks was ropivacaine 0.5% (9 mL in each of 2 levels) per side. We hypothesized that pectoralis-II blocks would have noninferior (1) analgesia [Numeric Rating Scale] and (2) cumulative opioid consumption within the operating and recovery rooms combined (dual primary outcomes). The study was adequately powered with n=100, but the target enrollment was raised to n=150 to account for higher-than-anticipated variability. RESULTS: The trial was ended prematurely with 119 (79%) of the original target of 150 participants enrolled due to (masked) surgeon preference. Within the recovery room, pain scores were higher in participants with pectoralis-II (n=60) than paravertebral blocks (n=59): median [IQR] 3.3 [2.3, 4.8] vs 1.3 [0, 3.6]; 95% CI: 0.5 to 2.6; P < 0.001. Similarly, intravenous morphine equivalents were higher in the pectoralis-II group: 17.5 [12.5, 21.9] vs 10.0 mg [10, 20]; 95% CI: 0.1 to 7.5; P = 0.004. No block-related adverse events were identified in either group. CONCLUSIONS: Following non-mastectomy breast surgery, 2-level paravertebral blocks provided superior analgesia and opioid sparing compared with pectoralis-II blocks. This is a contrary finding to the majority of studies in patients having mastectomy in which little significant difference was identified between the two types of blocks.

Oxone-Mediated Regioselective Oxy-iodination of 1-Aryl/Alkyl Butadienes Using TBAI.

A simple, mild, and environmentally benign regioselective oxy-iodination of 1-aryl/alkyl butadienes has been developed. While styrenes have been explored previously, this work on dienes has been highly regioselective and metal-free in oxy-iodination following Markovnikov's rule. The oxy-iodination products were obtained in good to excellent yields using various co-solvents (H2O, MeOH, EtOH, AcOH, etc.). In addition, the halohydrins have been useful building blocks in the synthesis of various functionalized keto iodides and azido alcohols.

A novel mathematical template for developing fDOM probe fluorescence signal correction models for freshwaters.

The reliable application of field deployable fluorescent dissolved organic matter (fDOM) probes is hindered by several influencing factors which need to be compensated. This manuscript describes the corrections of temperature, pH, turbidity and inner filter effect on fluorescence signal of a commercial fDOM probe (fDOMs). For this, Australian waters with wide ranging qualities were selected, e.g. dissolved organic carbon (DOC) ranging from ∼1 to ∼30 mg/L, specific UV absorbance at 254 nm from ∼1 to ∼6 L/m/mg and turbidity from ∼1 to ∼ 350 FNU. Laboratory-based model calibration experiments (MCEs) were performed. A model template was developed and used for the development of the correction models. For each factor, data generated through MCEs were used to determine model coefficient (α) values by fitting the generated model to the experimental data. Four discrete factor models were generated by determination of a factor-specific α value. The α values derived for each water of the MCEs subset were consistent for each factor model. This indicated generic nature of the four α values across wide-ranging water qualities. High correlation between fDOMs and DOC were achieved after applying the four-factor compensation models to new data (r, 0.96, p < 0.05). Also, average biases (and %) between DOC predicted through fDOMs and actual DOC were decreased by applying the four-factor compensation model (from 3.54 (60.9%) to 1.28 (16.7%) mg/L DOC). These correction models were incorporated into a Microsoft EXCEL-based software termed EXOf-Correct for ready-to-use applications.

A Narrative Review of Ultrasound-Guided and Landmark-based Percutaneous Cryoneurolysis for the Management of Acute and Chronic Pain.

PURPOSE OF REVIEW: Cryoneurolysis refers to the process of reversibly ablating peripheral nerves with extremely cold temperatures to provide analgesia for weeks to months. With ultrasound-guidance or landmark-based techniques, it is an effective modality for managing both acute and chronic pain. In this review, we summarize the reported literature behind its potential applications and efficacy. RECENT FINDINGS: Here, we summarize several studies (from case reports to clinical trials) describing the use of ultrasound-guided and landmark-based cryoneurolysis for acute and chronic pain. Acute pain indications included pain related to knee arthroplasty, limb amputations, mastectomies, shoulder surgery, rib fractures, and burn. Chronic pain indications included chronic knee pain (due to osteoarthritis), shoulder pain, painful neuropathies, postmastectomy pain syndrome, phantom limb pain, facial pain/headaches, foot/ankle pain, inguinal pain, and sacroiliac joint pain. For both acute and chronic pain indications, more high quality randomized controlled clinical trials are needed to definitively assess the efficacy of cryoneurolysis versus other standard therapies for a multitude of pain conditions.

Glucose-6-phosphate dehydrogenase deficiency as a cause for nonimmune hydrops fetalis and severe fetal anemia: A systematic review.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive disorder that predisposes individuals to hemolysis due to an inborn error of metabolism. We performed a systematic literature review to evaluate G6PD deficiency as a possible etiology of nonimmune hydrops fetalis (NIHF) and severe fetal anemia. METHODS: PubMed, OVID Medline, Scopus, and clinicaltrials.gov were queried from inception until 31 April 2023 for all published cases of NIHF and severe fetal anemia caused by G6PD deficiency. Keywords included "fetal edema," "hydrops fetalis," "glucose 6 phosphate dehydrogenase deficiency," and "fetal anemia." Cases with workup presuming G6PD deficiency as an etiology for NIHF and severe fetal anemia were included. PRISMA guidelines were followed. RESULTS: Five cases of G6PD-related NIHF and one case of severe fetal anemia were identified. Four fetuses (4/6, 66.7%) were male and two fetuses (2/6, 33.3%) were female. Mean gestational age at diagnosis of NIHF/anemia and delivery was 32.2 ± 4.9 and 35.7 ± 2.4 weeks, respectively. Four cases (66.7%) required a cordocentesis for fetal transfusion, and two cases (33.3%) received blood transfusions immediately following delivery. Among the four multigravida cases, two (50%) noted previous pregnancies complicated by neonatal anemia. When reported, the maternal cases included two G6PD deficiency carrier patients and two G6PD-deficient patients. Exposures to substances known to cause G6PD deficiency-related hemolysis occurred in 3/6 (50%) cases. CONCLUSION: Six cases of NIHF/severe fetal anemia were associated with G6PD deficiency. While G6PD deficiency is an X-linked recessive condition, female fetuses can be affected. Fetal G6PD deficiency testing can be considered if parental history indicates, particularly if the standard workup for NIHF is negative.

K2S2O8-Mediated or Azobisisobutyronitrile-Catalyzed Regioselective Aerobic Oxidative Cleavage of 1-Arylbutadienes to Cinnamaldehydes.

This work reveals the regioselective oxidative cleavage of 1-arylbutadienes to cinnamaldehydes mediated by K2S2O8 or catalyzed by azobisisobutyronitrile, a very common free radical initiator, in an easy to handle, simple procedure and free of transition metals. This approach demonstrates excellent regioselectivity, mild reaction conditions, and compatibility with a broad range of functional groups (45 examples).

Enhancing Laryngoscopy Mastery: The Impact of Autonomous Practice with Feedback-Providing Simulators.

Mastery learning with fixed end points and variable training time leads to more consistent expertise but is difficult to implement. Here we piloted mastery learning of laryngoscopy with independent practice. 35 learners participated in independent mastery learning on a manikin that provides automated performance feedback. A pre- and postpractice assessment of intubation skills was completed. After an average of 21 minutes of open practice, the percentage of subjects that met mastery criteria improved from 24% to 89% (P < .05). Independent intubation practice with manikin feedback facilitated mastery learning, enhanced procedural education, and may impact clinical care.

Cord blood troponin I levels: biomarker evidence of fetal cardiac injury in intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy has been linked to sudden stillbirth. The suddenness of the stillbirths in these cases have led clinicians to suspect that the pathogenesis of stillbirth in women with intrahepatic cholestasis of pregnancy is not related to asphyxia but rather to an undefined etiology. One leading hypothesis relates certain bile acid metabolites to myocardial injury. OBJECTIVE: The purpose of this study was to determine whether cord blood troponin I levels are increased in fetuses born to mothers with a diagnosis of intrahepatic cholestasis of pregnancy. STUDY DESIGN: A prospective, case-control study was performed at a single institution between 2017 to 2019 in which 87 pregnant patients with a diagnosis of intrahepatic cholestasis of pregnancy (total bile acids ≥10 µmol/L) were enrolled as cases and 122 randomly selected pregnant patients (asymptomatic with intrapartum total bile acids <10 µmol/L) were enrolled as controls. Cord blood troponin I levels were measured at delivery in both groups using a commercially available chemiluminescent immunoassay. Values ≤0.04 ng/mL were considered negative. Values >0.04 ng/mL were considered positive. The primary outcome was the presence of elevated troponin levels in both cases and controls as a surrogate marker for cardiac status. Our secondary outcomes included neonatal intensive care unit stay, low Apgar scores, neonatal acidosis, and hypoxia indicated by cord blood pH and base excess levels at the time of birth. Chi square and t tests were performed to compare social and obstetrical variables. A P value of <.05 was considered significant. A stratification by total bile acids range of <40 µmol/L, 40 to 100 µmol/L, and >100 µmol/L was performed to assess the relationship between the different severities of intrahepatic cholestasis of pregnancy (by risk of fetal demise with those with total bile acids of >100 µmol/L considered at greatest risk) and the likelihood of a positive troponin I result. Finally, a logistic regression analysis was performed to determine if levels of ≥10 µmol/L were associated with elevated troponin levels. RESULTS: The mean gestational age at delivery was 38.96±1.47 and 37.71±1.59 weeks of gestation in the controls and cases respectively (P<.001). The mean total bile acids values were 5.2±1.28 ng/mL and 43.2±40.62 ng/mL in the controls and cases respectively (P<.001). Cord blood troponin I was positive in 15 of 122 (12.30%) controls and in 20 of 87 (22.99%) cases. (P<.001). When further stratified by total bile acids levels of <40, 40 to 100, and >100 µmol/L, we found a positive correlation between higher total bile acids levels and a positive troponin I test (P=.002). When controlling for gestational age at delivery, maternal age, and body mass index, higher total bile acids levels were associated with a positive troponin I level (adjusted odds ratio, 1.015; 95% confidence interval, 1.004-1.026). CONCLUSION: Elevated troponin I was more likely to be found in patients with intrahepatic cholestasis of pregnancy than in those without intrahepatic cholestasis of pregnancy. When stratified by total bile acids levels, a positive troponin I level was more likely to be found with higher levels of total bile acids. In addition, as total bile acids levels increased, they were more likely to be associated with a positive troponin I level. Although there were no stillbirths in our cohort, our findings suggest a potential relationship between cardiac injury and high levels of total bile acids demonstrated by the presence of elevated troponin I levels in cord blood at the time of birth.

Stereoselective convergent total synthesis of oxylipins.

We synthesized stereoselectively four stereoisomers of oxylipins (1a-d) by a convergent approach based on chiral catalysis. The synthetic approach involved sequential assembly of two key fragments - ene-diol and allyl alcohol - for an intended convergent cross-metathesis reaction to join these fragments. The key steps include Sharpless kinetic resolution, asymmetric dihydroxylation and Grubbs cross-metathesis. The characterization of the synthesized oxylipins revealed spectroscopic data that were consistent with previously reported values.

A simple and scalable zebrafish model of Sonic hedgehog medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor in children and is stratified into three major subgroups. The Sonic hedgehog (SHH) subgroup represents ∼30% of all MB cases and has significant survival disparity depending upon TP53 status. Here, we describe a zebrafish model of SHH MB using CRISPR to create mutant ptch1, the primary genetic driver of human SHH MB. In these animals, tumors rapidly arise in the cerebellum and resemble human SHH MB by histology and comparative onco-genomics. Similar to human patients, MB tumors with loss of both ptch1 and tp53 have aggressive tumor histology and significantly worse survival outcomes. The simplicity and scalability of the ptch1-crispant MB model makes it highly amenable to CRISPR-based genome-editing screens to identify genes required for SHH MB tumor formation in vivo, and here we identify the gene encoding Grk3 kinase as one such target.

Associations Between Stroke Type, Ischemic Stroke Subtypes, and Post-Stroke Cognitive Trajectories.

Background: It is unclear how post-stroke cognitive trajectories differ by stroke type and ischemic stroke subtype. We studied associations between stroke types (ischemic, hemorrhagic), ischemic stroke subtypes (cardioembolic, large artery atherosclerotic, lacunar/small vessel, cryptogenic/other determined etiology), and post-stroke cognitive decline. Methods: This pooled cohort analysis from four US cohort studies (1971-2019) identified 1,143 dementia-free individuals with acute stroke during follow-up: 1,061 (92.8%) ischemic, 82 (7.2%) hemorrhagic, 49.9% female, 30.8% Black. Median age at stroke was 74.1 (IQR, 68.6, 79.3) years. Outcomes were change in global cognition (primary) and changes in executive function and memory (secondary). Outcomes were standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median follow-up for the primary outcome was 6.0 (IQR, 3.2, 9.2) years. Linear mixed-effects models estimated changes in cognition after stroke. Results: On average, the initial post-stroke global cognition score was 50.78 points (95% CI, 49.52, 52.03) in ischemic stroke survivors and did not differ in hemorrhagic stroke survivors (difference, -0.17 points [95% CI, -1.64, 1.30]; P=0.82) after adjusting for demographics and pre-stroke cognition. On average, ischemic stroke survivors showed declines in global cognition, executive function, and memory. Post-stroke declines in global cognition, executive function, and memory did not differ between hemorrhagic and ischemic stroke survivors. 955 ischemic strokes had subtypes: 200 (20.9%) cardioembolic, 77 (8.1%) large artery atherosclerotic, 207 (21.7%) lacunar/small vessel, 471 (49.3%) cryptogenic/other determined etiology. On average, small vessel stroke survivors showed declines in global cognition and memory, but not executive function. Initial post-stroke cognitive scores and cognitive declines did not differ between small vessel survivors and survivors of other ischemic stroke subtypes. Post-stroke vascular risk factor levels did not attenuate associations. Conclusion: Stroke survivors had cognitive decline in multiple domains. Declines did not differ by stroke type or ischemic stroke subtype.