Total Hip Arthroplasty in Patients Who Have Factor V Leiden: Elevated Risks Isolated to Venous Thromboembolism Events.

BACKGROUND: Total hip arthroplasty (THA) is a common procedure that requires consideration of preexisting comorbidities. Factor V Leiden (FVL), an inherited thrombophilia, is one such condition that predisposes patients to venous thromboembolism (VTE, deep vein thrombosis, and pulmonary embolism). The present study aimed to characterize the risks associated with FVL patients undergoing THA and evaluate the effect of VTE chemoprophylactic agents on these risks. METHODS: A total of 544,022 adult patients who underwent primary THA for osteoarthritis indications between 2010 and October 2021 were identified in an administrative claims database. Of these, FVL was identified in 1,138 (0.21%). Patients who had and did not have FVL were matched at a 1:4 ratio (1,131 with FVL and 4,519 without FVL) based on age, sex, and Elixhauser comorbidity index. Univariable and multivariable analyses were assessed for 90-day complications. Implant survival at 5 years was assessed and compared with log-rank tests. The relative use of different chemoprophylactic agents, including aspirin, warfarin, heparin, or direct oral anticoagulant (DOAC), was assessed. Bleeding events and VTE were compared for those prescribed either aspirin or warfarin, heparin, or DOAC. A Bonferroni correction was applied. RESULTS: On multivariable analysis, FVL patients were found to have increased odds of 90-day deep vein thrombosis (odds ratio (OR) = 9.20), pulmonary embolism (OR = 6.89), and aggregated severe and all adverse events (OR = 4.74 and 1.98, respectively), but not elevated risk of other perioperative adverse events or 5-year reoperations. More potent chemoprophylactic agents (warfarin, heparin, DOAC) reduced, but did not completely eliminate, the increased VTE risks (without increasing bleeding events). CONCLUSIONS: This study quantified the significantly elevated VTE risk associated with FVL patients undergoing THA. The lack of difference in other specific adverse events and 5-year reoperations is reassuring. Clearly, chemoprophylactic agents are important in this population and may need further attention.

Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy.

Spinal Muscular Atrophy (SMA) is typically characterized as a motor neuron disease, but extra-neuronal phenotypes are present in almost every organ in severely affected patients and animal models. Extra-neuronal phenotypes were previously underappreciated as patients with severe SMA phenotypes usually died in infancy; however, with current treatments for motor neurons increasing patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to new treatment-modified phenotypes. Fatty liver is seen in SMA animal models , but generalizability to patients and whether this is due to hepatocyte-intrinsic Survival Motor Neuron (SMN) protein deficiency and/or subsequent to skeletal muscle denervation is unknown. If liver pathology in SMA is SMN-dependent and hepatocyte-intrinsic, this suggests SMN repleting therapies must target extra-neuronal tissues and motor neurons for optimal patient outcome. Here we showed that fatty liver is present in SMA and that SMA patient-specific iHeps were susceptible to steatosis. Using proteomics, functional studies and CRISPR/Cas9 gene editing, we confirmed that fatty liver in SMA is a primary SMN-dependent hepatocyte-intrinsic liver defect associated with mitochondrial and other hepatic metabolism implications. These pathologies require monitoring and indicate need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.

Risk of Adverse Events Following Total Knee Arthroplasty in Asthma Patients.

INTRODUCTION: Total knee arthroplasty (TKA) is a common procedure for which patient factors are known to affect perioperative outcomes. Asthma has not been specifically considered in this regard, although it is the most common inflammatory airway disease and predisposes to osteoarthritis. METHODS: Adult patients undergoing TKA were identified from 2015 to 2021-Q3 M157 PearlDiver data sets. Asthma patients were matched to those without 1:1 based on age, sex, and Elixhauser Comorbidity Index (ECI). The incidence of 90-day adverse events and 5-year revisions were compared using multivariable logistic regression ( P < 0.0023). The matched asthma group was then stratified based on disease severity for analysis of 90-day aggregated (any, severe, and minor) adverse events. RESULTS: Among 721,686 TKA patients, asthma was noted for 76,125 (10.5%). Multivariable analysis revealed that patients with asthma were at increased odds of multiple 90-day pulmonary, non-pulmonary, and aggregated adverse events, as well as emergency department visits. Furthermore, patients with asthma had 1.17 times greater odds of 5-year revisions ( P < 0.0001). Upon secondary analysis stratifying asthma by severity, patients with all severity levels of asthma showed elevated odds of adverse events after TKA. These associations increased in odds with increasing severity of asthma. DISCUSSION: Over one-tenth of patients undergoing TKA were identified as having asthma, and these patients were at greater odds of numerous pulmonary and non-pulmonary adverse events (a trend that increased with asthma severity), as well as 5-year revisions. Clearly, patients with asthma need specific risk mitigation strategies when considering TKA. LEVEL OF EVIDENCE: III.

Outcomes Following Total Hip Arthroplasty in Patients Who Have Von Willebrand Disease Depend on Postoperative Anticoagulation.

BACKGROUND: Von Willebrand disease (VWD) is the most common congenital bleeding disorder. This autosomal dominant condition arises from quantitative or qualitative defects of Von Willebrand factor. To our knowledge, this study leveraged a national database to characterize the largest VWD cohort of total hip arthroplasty (THA) patients to date, assessing 90-day postoperative adverse events and 5-year revision-free survival. METHODS: Adult patients who underwent primary THA for osteoarthritis were identified from January 2010 to October 2021 in a nationwide database. Patients who had and did not have VWD were matched (4:1) on age, sex, and Elixhauser Comorbidity Index and compared with multivariable logistic regression. Patients were then categorized based upon venous thromboembolism (VTE) chemoprophylaxis prescription patterns to compare bleeding and thrombotic adverse events. RESULTS: Of 544,851 THA patients, VWD was identified in 309 patients (0.06%). The matched cohorts contained 1,221 patients who did not have VWD and 306 patients who have VWD. On multivariable analysis, VWD patients had increased odds of 90-day VTE (odds ratio [OR] = 1.86) and hematoma (OR = 3.40) (P < .05 for all). No difference in 5-year revision-free survival was found. The VWD patients receiving aspirin or no prescriptions had greater odds of VTE (OR = 2.39, P = .048). Those on other chemoprophylaxis agents had greater odds of hematoma (OR = 4.84, P = .006). CONCLUSIONS: Patients with VWD undergoing THA had increased odds of 90-day VTE if using aspirin or no prescriptions, or hematoma if using other chemoprophylaxis. There is a delicate balancing act of clotting versus bleeding that must be considered in managing such patients, but it was reassuring that no difference in overall 5-year revision-free survival was found.

Patients With Cystic Fibrosis Undergoing Total Hip and Total Knee Arthroplasty Are at Increased Risk for Perioperative Complications.

INTRODUCTION: Patients with cystic fibrosis (CF) are living longer and may be considered for total hip arthroplasty (THA) or total knee arthroplasty (TKA). Perioperative outcomes and implant survival after these procedures performed for those with CF have not been previously described. METHODS: Using the M151 PearlDiver database, a large, national, administrative database, THA and TKA patients with and without CF were identified and matched 1:10 based on age, sex, and Elixhauser Comorbidity Index. Ninety-day perioperative outcomes and 2-year revision rates were assessed and compared with multivariable logistic regression. RESULTS: For THA, 185 patients with CF were matched with 1,846 control subjects without CF. Patients with CF were at significantly increased odds of 90-day postoperative events including sepsis (odd radio [OR] 4.15), pneumonia (OR 3.40), pleural effusion (OR 2.77), minor events (OR 1.73), any adverse event (OR 1.64), urinary tract infection (UTI) (OR 1.63), and severe events (OR 1.60) ( P < 0.05 for each). For TKA, 505 patients with CF were matched with 5,047 control subjects without CF. Patients with CF were at significantly increased odds of 90-day postoperative events including pneumonia (OR 4.95), respiratory failure (OR 4.31), cardiac event (OR 2.29), minor events (OR 2.16), pleural effusion (OR 2.35), severe events (OR 2.06), urinary tract infection (OR 2.06), any adverse event (OR 1.96), atelectasis (OR 1.94), and acute kidney injury (OR 1.61) ( P < 0.05 for each). For both THA and TKA, those with CF were not at greater odds of 2-year rates of revision. DISCUSSION: After THA and TKA, those with CF were found to be at increased odds of multiple defined postoperative events (predominantly infectious/pulmonary), but not 2-year revision rates. These findings help define areas in need of focused optimization and are reassuring regarding risks of surgery.

Increasing Value in Subspecialty Training: A Comparison of Variation in Surgical Complications for Pediatric Versus Other Fellowship-trained American Board of Orthopaedic Surgery Candidates in the Treatment of Supracondylar Fractures.

INTRODUCTION: The effect of orthopaedic fellowship subspecialization on surgical complications for patients with supracondylar fracture is unknown. This study seeks to compare the effect of subspecialty training on supracondylar fracture complications. METHODS: The American Board of Orthopaedic Surgery Part II Examination Case List database was reviewed for all supracondylar fractures from 1999 to 2016. Procedures were divided by fellowship subspecialty (trauma, pediatric, or other) and case volume and assessed by surgeon-reported surgical complications. Predictive factors of complications were analyzed using a binary multivariate logistic regression. RESULTS: Of 10,961 supracondylar fractures identified, 53.47% were done by pediatric fellowship-trained surgeons. Pediatric-trained surgeons had fewer surgical complications compared with their trauma or other trained peers (4.54%, 5.67%, and 6.24%; P = 0.001). Treatment by pediatric-trained surgeons reduced surgical complications (OR = 0.79, 95% CI: 0.66 to 0.94; P = 0.010), whereas increased case volume (31+ cases) showed no significant effect (OR = 0.79, 95% CI: 0.62 to 1.02; P = 0.068). Patient sex, age, and year of procedure did not affect complication rates, while those treated in the Southeast region of the United States and those with a complex fracture type were at increased odds. DISCUSSION: Treatment of supracondylar fractures by pediatric-trained surgeons demonstrates reduced surgeon-reported complications compared with their other fellowship-trained counterparts, whereas case volume does not. This suggests the value of fellowship training beyond pertinent surgical caseload among pediatric-trained surgeons and may lie in targeted education efforts.

Patients With Down Syndrome and Total Hip and Total Knee Arthroplasty: Outcome Measures Show Increased Risk of Perioperative Complications.

BACKGROUND: Patients with Down syndrome (DS) are being considered for total joint arthroplasty. There is limited literature regarding outcomes of patients with DS after total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: Data were abstracted from the 2010 to 2021 Q1 PearlDiver M151 database. THA and TKA osteoarthritis adult patients with and without DS were identified. Patients were matched 1:10. Ninety-day postoperative events and 2-year revision rates were compared. RESULTS: For THA, 154 patients with DS were matched with 1,532 patients without DS. For TKA, 150 patients with DS were matched with 1,495 patients without DS. On multivariable logistic regression, THA and TKA patients with DS were at markedly greater odds of postoperative events including any adverse event, sepsis, minor adverse event, urinary tract infection (UTI), acute kidney injury (AKI), and pneumonia. For both THA and TKA, 2-year revision rates were not increased for those with DS. DISCUSSION: This study represents the largest cohorts for matched patients with DS undergoing THA or TKA through 90 days postoperatively. For both procedures, DS patients were found to have greater risk of several adverse events, but not 2-year revisions. These findings may help guide perioperative risk assessment, patient/family counseling, and care pathways.

Total Hip Arthroplasty in Patients Who Have Marfan Syndrome: Adverse Events and 5-Year Revision Rates.

BACKGROUND: Marfan syndrome is a rare inherited connective tissue disease, which may be present in patients who have advanced hip pathologies that may require total hip arthroplasty (THA). The postoperative course of patients who have Marfan syndrome following THA has not yet been defined. METHODS: Adult patients who have and do not have Marfan syndrome and underwent THA were identified in a national database. Patients diagnosed who had infection, trauma, or neoplasms within the 90 days prior to surgery were excluded. Those who have versus those who did not have Marfan syndrome were matched 1:10 based on age, sex, and a comorbidity index. After matching, 144 patients who have Marfan syndrome and 1,440 who do not have Marfan syndrome were identified. The 90-day postoperative adverse events and 5-year revisions were assessed and compared with multivariable analyses and log rank tests, respectively. RESULTS: Multivariable analyses demonstrated that Marfan syndrome was independently associated with greater odds of 90-day adverse events: venous thromboembolic events (odds ratio [OR]: 2.9, P = .001), cardiac events (OR: 4.5, P = .034), pneumonia (OR: 3.5, P < .001), and urinary tract infections (OR: 5.2, P < .001). There was no significant difference in 5-year rates of revision. CONCLUSIONS: Following THA, Marfan syndrome was independently associated with greater rates of several 90-day adverse events, but not higher 5-year rates of revision. The identified at-risk adverse events may help guide surgeons to improve perioperative care pathways, while having confidence regarding joint survival of THA in this rare disease population.

Emergency Department Visits Following Patellofemoral Arthroplasty.

BACKGROUND: Readmissions are a typical postoperative metric; however, postoperative emergency department (ED) utilization also negatively affects patient care. Few studies have explored this metric after patellofemoral arthroplasty (PFA); thus, we investigated the incidence, timing, predictive factors, and reasons for ED utilization within 90 days after PFA. METHODS: Using the 2010 to 2021 PearlDiver M151Ortho data set, a national billing claims database containing information of over 151 million US orthopaedic patients across all payer types, the study examined weekly ED visits up to 90 days after PFA and conducted univariate and multivariate analyses to identify predictive factors. RESULTS: Of 7765 PFA patients, 11.2% (922) had ED visits within 90 days, with 46.7% (431) occurring in the first 3 weeks. Independent predictors of ED utilization included younger age (OR 1.40 per decade decrease), higher Elixhauser Comorbidity Index (OR 1.44 per 2-point increase), surgery in the South or Midwest (OR 1.27 and 1.31), and Medicaid insurance (OR 1.74). Postoperative pain accounted for 50.6% of visits. CONCLUSIONS: 11.2% of PFA patients visited the ED within 90 days, primarily for postoperative pain. Younger, more comorbid, and Medicaid-insured patients were most likely to use the ED. This study suggests the need for targeted perioperative pain management to reduce ED utilization after PFA.

Robust induction of functional astrocytes using NGN2 expression in human pluripotent stem cells.

Emerging evidence of species divergent features of astrocytes coupled with the relative inaccessibility of human brain tissue underscore the utility of human pluripotent stem cell (hPSC) technologies for the generation and study of human astrocytes. However, existing approaches for hPSC-astrocyte generation are typically lengthy or require intermediate purification steps. Here, we establish a rapid and highly scalable method for generating functional human induced astrocytes (hiAs). These hiAs express canonical astrocyte markers, respond to pro-inflammatory stimuli, exhibit ATP-induced calcium transients and support neuronal network development. Moreover, single-cell transcriptomic analyses reveal the generation of highly reproducible cell populations across individual donors, mostly resembling human fetal astrocytes. Finally, hiAs generated from a trisomy 21 disease model identify expected alterations in cell-cell adhesion and synaptic signaling, supporting their utility for disease modeling applications. Thus, hiAs provide a valuable and practical resource for the study of basic human astrocyte function and dysfunction in disease.

Management of Bilateral Synchronous Knee Prosthetic Joint Infection in a Patient with Infected Heart Transplant: A Case Report.

CASE: A 74-year-old man presented with septic shock with infection of his heart transplant and bilateral prosthetic knee joints simultaneously. He underwent bilateral knee resection arthroplasties with placement of articulating spacers. At 3-year follow-up, the patient was alive and ambulating independently. CONCLUSION: This case represents the first report of bilateral hematogenous prosthetic knee infections associated with concomitant enterococcal endocarditis of a heart transplant treated successfully and definitively with radical debridement and placement of articulating spacer with regular implants.

Total Knee Arthroplasty: Variables Affecting 90-day Overall Reimbursement.

BACKGROUND: Total knee arthroplasty (TKA) is commonly considered to address symptomatically limiting knee osteoarthritis. With increasing utilization, understanding the variability and related drivers may help the healthcare system optimize delivery to the large numbers of patient to whom it is offered. METHODS: A total of 1,066,327 TKA patients who underwent primary TKA were isolated from a 2010 to 2021 PearlDiver national dataset. Exclusion criteria included patients less than 18 years old and traumatic, infectious, or oncologic indications. Overall, 90-day reimbursements and variables associated with the patient, surgical procedure, region, and perioperative period were abstracted. Multivariable linear regressions were performed to determine independent drivers of reimbursement. RESULTS: The 90-day postoperative reimbursements had an average (standard deviation) of $11,212.99 ($15,000.62), a median (interquartile range) of $4,472.00 ($13,101.00), and a total of $11,946,962,912. Variables independently associated with the greatest increase in overall 90-day reimbursement were related to admission (in-patient index-procedure [+$5,695.26] or hospital readmission [+$18,495.03]). Further drivers were region (Midwest +$8,826.21, West +$4,578.55, South +$3,709.40; relative to Northeast), insurance (commercial +$4,492.34, Medicaid +$1,187.65; relative to Medicare), postoperative emergency department visits (+$3,574.57), postoperative adverse events (+$1,309.35), (P < .0001 for each). CONCLUSION: The current study assessed over a million TKA patients and found large variations in reimbursement/cost. The largest increases in reimbursement were associated with admission (readmission or index procedure). This was followed by region, insurance, and other postoperative events. These results underscore the necessity to balance performing out-patient surgeries in appropriate patients versus the risk of readmissions and defined other areas for cost containment strategies.

Urgent Care Visits Sought After Primary Total Hip Arthroplasty: A Potentially Overlooked Resource.

BACKGROUND: Following total hip arthroplasty (THA), readmissions and emergency department (ED) visits have been studied. Urgent care utilization is not well-characterized and may represent an overlooked avenue to facilitate lesser acuity patient needs. METHODS: Primary THAs performed for osteoarthritis indications were identified from 2010 to April of 2021 from a large national database. The incidence and timing of 90-day postoperative ED and urgent care visits were determined. Univariable and multivariable analyses assessed factors associated with urgent care relative to ED utilization. Reasons and acuity of diagnoses for these visits were determined. For 213,189 THA patients, 90-day ED visits were identified for 37,692 (17.7%) and urgent care visits for 2,083 (1.0%). The greatest incidence of both ED and urgent care visits were in the first two postoperative weeks. RESULTS: Independent predictors of urgent care utilization relative to ED utilization were: procedures being performed in the Northeast or South, insurance plan being Commercial, women, and lesser comorbidity burden (P < .0001). Reason for visits to the ED was directly related to the surgical site for 25.6% but for urgent care were just 4.8% (P < .0001). Reasons for visits to the ED were classified as low-acuity for 57.4% and for urgent care 96.9% (P < .0001). CONCLUSION: Following THA, patients may need urgent evaluation. While many issues can be addressed through the office, urgent care visits may represent a viable and underused resource relative to the ED for a large percentage of patients who have lower acuity diagnoses.

Comparing Race/Ethnicity and Zip Code Socioeconomic Status for Surgical versus Nonsurgical Management of Proximal Humerus Fractures in a Medicare Population.

BACKGROUND: This study evaluated the effect of race/ethnicity and socioeconomic status (SES) on surgical utilization after proximal humerus fractures in a large Medicare cohort. METHODS: The PearlDiver Medicare claims database was used to identify patients aged 65years and older with isolated, closed proximal humerus fractures, for whom race/ethnicity data were available (65.5% of identified fractures). Patients with polytrauma or neoplasm were excluded. Patient demographic, race/ethnicity, comorbidity, and median household income were compared for surgical versus nonsurgical management. Univariate and multivariable logistic regressions were used to determine disparities of surgical utilization based on the abovementioned factors. RESULTS: Of 133,218 patients with proximal humerus fracture identified, surgery was conducted for 4446 (3.3%). Those less likely to receive surgery were older (incrementally by increasing age bracket up to 85 years and older odds ratio [OR], 0.16, P < 0.001), male (OR, 0.79, P < 0.001), Black (OR, 0.51, P < 0.001) or Hispanic (0.61, P = 0.005), higher Elixhauser Comorbidity Index (per 2 increase OR, 0.86, P < 0.001), and low median household income (OR, 0.79, P < 0.001). CONCLUSIONS: The independent significance of race/ethnicity and SES point to disparities in surgical decision making/access to care. These findings highlight the need for increased attention on initiatives and policies that seek to eliminate racial disparities and improve health equity independent of SES.

Implementation of a Drug Screening Platform to TargetGch1 Expression in Injured Mouse Dorsal Root Ganglion Neurons.

Management of neuropathic pain is notoriously difficult; current analgesics, including anti-inflammatory- and opioid-based medications, are generally ineffective and can pose serious side effects. There is a need to uncover non-addictive and safe analgesics to combat neuropathic pain. Here, we describe the setup of a phenotypic screen whereby the expression of an algesic gene,Gch1, is targeted. GCH1 is the rate-limiting enzyme in the de novo synthesis of tetrahydrobiopterin (BH4), a metabolite linked to neuropathic pain in both animal models and in human chronic pain sufferers.Gch1is induced in sensory neurons after nerve injury and its upregulation is responsible for increased BH4 levels. GCH1 protein has proven to be a difficult enzyme to pharmacologically target with small molecule inhibition. Thus, by establishing a platform to monitor and target inducedGch1 expression in individual injured dorsal root ganglion (DRG) neurons in vitro, we can screen for compounds that regulate its expression levels. This approach also allows us to gain valuable biological insights into the pathways and signals regulating GCH1 and BH4 levels upon nerve injury. This protocol is compatible with any transgenic reporter system in which the expression of an algesic gene (or multiple genes) can be monitored fluorescently. Such an approach can be scaled up for high-throughput compound screening and is amenable to transgenic mice as well as human stem cell-derived sensory neurons. Graphical overview.

Magnetic Resonance Imaging in the Year Prior to Total Knee Arthroplasty: A Potential Overutilization of Healthcare Resources.

BACKGROUND: Total knee arthroplasty (TKA) is a common procedure for late-stage degenerative changes, a situation for which magnetic resonance imaging (MRI) is typically not considered useful. In an era attempting to contain healthcare expenditures, the rate, timing, and predictors for MRI before TKA were assessed in a large, national, administrative data set. METHODS: The 2010 to Q3 2020 MKnee PearlDiver data set was used to identify patients undergoing TKA for osteoarthritis. Those with lower extremity MRI for knee indications within 1 year before TKA were then defined. Patient age, sex, Elixhauser Comorbidity Index, region in the country, and insurance plan were characterized. Predictors of having had an MRI were assessed by univariate and multivariate analyses. The costs and timing of the obtained MRIs were also assessed. RESULTS: Of 731,066 TKAs, MRI was obtained within 1 year prior for 56,180 (7.68%) with 28,963 (51.9%) within the 3 months of TKA. Independent predictors of having had an MRI included younger age (odds ratio [OR], 0.74 per decade increase), female sex (OR, 1.10), higher Elixhauser Comorbidity Index (OR, 1.15), region of the country (relative to South, Northeast OR, 1.08, West OR, 1.22, Midwest OR, 1.36), and insurance (relative to Medicare, Medicaid OR, 1.36 and Commercial OR, 1.35) with P < 0.0001 for each. The total cost of MRIs among patients who received a TKA is $44,686,308. CONCLUSION: Noting that TKA is typically done for advanced degenerative changes, MRI should rarely be indicated in the preoperative period for this procedure. Nonetheless, this study found that MRI was done within the year before TKA for 7.68% of the study cohort. In an era striving for evidence-based medicine, the almost $45 million dollars spent on MRI in the year before TKA may represent overutilization.

A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides.

Parkinson's disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson's-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.

High-content synaptic phenotyping in human cellular models reveals a role for BET proteins in synapse assembly.

Resolving fundamental molecular and functional processes underlying human synaptic development is crucial for understanding normal brain function as well as dysfunction in disease. Based upon increasing evidence of species-divergent features of brain cell types, coupled with emerging studies of complex human disease genetics, we developed the first automated and quantitative high-content synaptic phenotyping platform using human neurons and astrocytes. To establish the robustness of our platform, we screened the effects of 376 small molecules on presynaptic density, neurite outgrowth, and cell viability, validating six small molecules that specifically enhanced human presynaptic density in vitro. Astrocytes were essential for mediating the effects of all six small molecules, underscoring the relevance of non-cell-autonomous factors in synapse assembly and their importance in synaptic screening applications. Bromodomain and extraterminal (BET) inhibitors emerged as the most prominent hit class and global transcriptional analyses using multiple BET inhibitors confirmed upregulation of synaptic gene expression. Through these analyses, we demonstrate the robustness of our automated screening platform for identifying potent synaptic modulators, which can be further leveraged for scaled analyses of human synaptic mechanisms and drug discovery efforts.

Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types.

Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains after parabiosis. For each cell type, we cataloged alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions and senescence status. Our analyses identified gene signatures, demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest new strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors.