Neuroinflammatory gene expression profiles of reactive glia in the substantia nigra suggest a multidimensional immune response to alpha synuclein inclusions.

Parkinson's disease (PD) pathology is characterized by alpha-synuclein (α-syn) aggregates, degeneration of dopamine neurons in the substantia nigra pars compacta (SNpc), and neuroinflammation. The presence of reactive glia correlates with deposition of pathological α-syn in early-stage PD. Thus, understanding the neuroinflammatory response of microglia and astrocytes to synucleinopathy may identify therapeutic targets. Here we characterized the neuroinflammatory gene expression profile of reactive microglia and astrocytes in the SNpc during early synucleinopathy in the rat α-syn pre-formed fibril (PFF) model. Rats received intrastriatal injection of α-syn PFFs and expression of immune genes was quantified with droplet digital PCR (ddPCR), after which fluorescent in situ hybridization (FISH) was used to localize gene expression to microglia or astrocytes in the SNpc. Genes previously associated with reactive microglia (Cd74, C1qa, Stat1, Axl, Casp1, Il18, Lyz2) and reactive astrocytes (C3, Gbp2, Serping1) were significantly upregulated in the SN of PFF injected rats. Localization of gene expression to SNpc microglia near α-syn aggregates identified a unique α-syn aggregate microglial gene expression profile characterized by upregulation of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, C3, C1qa, Serping1 and Fcer1g. Importantly, significant microglial upregulation of Cd74 and C3 were only observed following injection of α-syn PFFs, not α-syn monomer, confirming specificity to α-syn aggregation. Serping1 expression also localized to astrocytes in the SNpc. Interestingly, C3 expression in the SNpc localized to microglia at 2- and 4-months post-PFF, but to astrocytes at 6-months post-PFF. We also observed expression of Rt1-a2 and Cxcl10 in SNpc dopamine neurons. Cumulatively our results identify a dynamic, yet reproducible gene expression profile of reactive microglia and astrocytes associated with early synucleinopathy in the rat SNpc.

Deficits in basal and evoked striatal dopamine release following alpha-synuclein preformed fibril injection: An in vivo microdialysis study.

Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) protein, forming intraneuronal Lewy body (LB) inclusions. The α-syn preformed fibril (PFF) model of PD recapitulates α-syn aggregation, progressive nigrostriatal degeneration and motor dysfunction; however, little is known about the time course of PFF-induced alterations in basal and evoked dopamine (DA). In vivo microdialysis is well suited for identifying small changes in neurotransmitter levels over extended periods. In the present study, adult male Fischer 344 rats received unilateral, intrastriatal injections of either α-syn PFFs or phosphate-buffered saline (PBS). At 4 or 8 months post-injection (p.i.), animals underwent in vivo microdialysis to evaluate basal extracellular striatal DA and metabolite levels, local KCl-evoked striatal DA release and the effects of systemic levodopa (l-DOPA). Post-mortem analysis demonstrated equivalent PFF-induced reductions in tyrosine hydroxylase (TH) immunoreactive nigral neurons (~50%) and striatal TH (~20%) at both time points. Compared with reduction in striatal TH, reduction in striatal dopamine transporter (DAT) was more pronounced and progressed between the 4- and 8-month p.i. intervals (36% âž” 46%). Significant PFF-induced deficits in basal and evoked striatal DA, as well as deficits in motor performance, were not observed until 8 months p.i. Responses to l-DOPA did not differ regardless of PBS or PFF treatment. These results suggest that basal and evoked striatal DA are maintained for several months following PFF injection, with loss of both associated with motor dysfunction. Our studies provide insight into the time course and magnitude of PFF-induced extracellular dopaminergic deficits in the striatum.

Alpha-synuclein inclusion responsive microglia are resistant to CSF1R inhibition.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies), markers of neuroinflammation and the progressive loss of nigrostriatal dopamine (DA) neurons. These pathological features can be recapitulated in vivo using the α-syn preformed fibril (PFF) model of synucleinopathy. We have previously determined that microglia proximal to PFF-induced nigral α-syn inclusions increase in soma size, upregulate major-histocompatibility complex-II (MHC-II) expression, and increase expression of a suite of inflammation-associated transcripts. This microglial response is observed months prior to degeneration, suggesting that microglia reacting to α-syn inclusion may contribute to neurodegeneration and could represent a potential target for novel therapeutics. The goal of this study was to determine whether colony stimulating factor-1 receptor (CSF1R)-mediated microglial depletion impacts the magnitude of α-syn aggregation, nigrostriatal degeneration, or the response of microglial in the context of the α-syn PFF model. METHODS: Male Fischer 344 rats were injected intrastriatally with either α-syn PFFs or saline. Rats were continuously administered Pexidartinib (PLX3397B, 600 mg/kg), a CSF1R inhibitor, to deplete microglia for a period of either 2 or 6 months. RESULTS: CSF1R inhibition resulted in significant depletion (~ 43%) of ionized calcium-binding adapter molecule 1 immunoreactive (Iba-1ir) microglia within the SNpc. However, CSF1R inhibition did not impact the increase in microglial number, soma size, number of MHC-II immunoreactive microglia or microglial expression of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, and Fcer1g associated with phosphorylated α-syn (pSyn) nigral inclusions. Further, accumulation of pSyn and degeneration of nigral neurons was not impacted by CSF1R inhibition. Paradoxically, long term CSF1R inhibition resulted in increased soma size of remaining Iba-1ir microglia in both control and PFF rats, as well as expression of MHC-II in extranigral regions. CONCLUSIONS: Collectively, our results suggest that CSF1R inhibition does not impact the microglial response to nigral pSyn inclusions and that CSF1R inhibition is not a viable disease-modifying strategy for PD.

AAV9-Mediated Intra-Striatal Delivery of GNAO1 Reduces Hyperlocomotion in Gnao1 Heterozygous R209H Mutant Mice.

Mutations in the GNAO1 gene, which encodes the abundant brain G-protein Gαo, result in neurologic disorders characterized by developmental delay, epilepsy, and movement abnormalities. There are over 50 mutant alleles associated with GNAO1 disorders; the R209H mutation results in dystonia, choreoathetosis, and developmental delay without seizures. Mice heterozygous for the human mutant allele (Gnao1 +/R209H) exhibit hyperactivity in open field tests but no seizures. We developed self-complimentary adeno-associated virus vectors (scAAV9) expressing two splice variants of human GNAO1 Gαo isoforms 1 (GoA, GNAO1.1) and 2 (GoB, GNAO1.2). Bilateral intra-striatal injections of either scAAV9-GNAO1.1 or scAAV9-GNAO1.2 significantly reversed mutation-associated hyperactivity in open field tests. GNAO1 overexpression did not increase seizure susceptibility, a potential side-effect of GNAO1 vector treatment. This represents the first report of successful preclinical gene therapy for GNAO1 encephalopathy applied in vivo Further studies are needed to uncover the molecular mechanism that results in behavior improvements after scAAV9-mediated Gαo expression and to refine the vector design. Significance Statement GNAO1 mutations cause a spectrum of developmental, epilepsy, and movement disorders. Here, we show that intra-striatal delivery of scAAV9-GNAO1 to express the wild-type Gαo protein reduces the hyperactivity of the Gnao1 +/R209H mouse model, which carries one of the most common movement disorder-associated mutations. This is the first report of a gene therapy for GNAO1 encephalopathy applied in vivo on a patient-allele model.

Liquid-liquid phase separation induced auto-confinement.

Confinement allows macromolecules and biomacromolecules to attain arrangements typically unachievable through conventional self-assembly processes. In the field of block copolymers, confinement has been achieved by preparing thin films and controlled solvent evaporation through the use of emulsions. A significant advantage of the confinement-driven self-assembly process is its ability to enable block copolymers to form particles with complex internal morphologies, which would otherwise be inaccessible. Here, we show that liquid-liquid phase separation (LLPS) can induce confinement during the self-assembly of a model block copolymer system. Since this confinement is driven by the block copolymers' tendency to undergo LLPS, we define this confinement type as auto-confinement. This study adds to the growing understanding of how LLPS influences block copolymer self-assembly and provides a new method to achieve confinement driven self-assembly.

Hybrid Photoiniferter and Ring-Opening Polymerization Yields One-Pot Anisotropic Nanorods.

Polymerization-induced self-assembly (PISA) has emerged as a scalable one-pot technique to prepare block copolymer (BCP) nanoparticles. Recently, a PISA process, that results in poly(l-lactide)-b-poly(ethylene glycol) BCP nanoparticles coined ring-opening polymerization (ROP)-induced crystallization-driven self-assembly (ROPI-CDSA), was developed. The resulting nanorods demonstrate a strong propensity for aggregation, resulting in the formation of 2D sheets and 3D networks. This article reports the synthesis of poly(N,N-dimethyl acrylamide)-b-poly(l)-lactide BCP nanoparticles by ROPI-CDSA, utilizing a two-step, one-pot approach. A dual-functionalized photoiniferter is first used for controlled radical polymerization of the acrylamido-based monomer, and the resulting polymer serves as a macroinitiator for organocatalyzed ROP to form the solvophobic polyester block. The resulting nanorods are highly stable and display anisotropy at higher molecular weights (>12k Da) and concentrations (>20% solids) than the previous report. This development expands the chemical scope of ROPI-CDSA BCPs and provides readily accessible nanorods made with biocompatible materials.

Understanding and controlling the nucleation and growth of metal-organic frameworks.

Metal-organic frameworks offer a diverse landscape of building blocks to design high performance materials for implications in almost every major industry. With this diversity stems complex crystallization mechanisms with various pathways and intermediates. Crystallization studies have been key to the advancement of countless biological and synthetic systems, with MOFs being no exception. This review provides an overview of the current theories and fundamental chemistry used to decipher MOF crystallization. We then discuss how intrinsic and extrinsic synthetic parameters can be used as tools to modulate the crystallization pathway to produce MOF crystals with finely tuned physical and chemical properties. Experimental and computational methods are provided to guide the probing of MOF crystal formation on the molecular and bulk scale. Lastly, we summarize the recent major advances in the field and our outlook on the exciting future of MOF crystallization.

Stability before and after percutaneous anterior medullary fixation of lateral compression 1 and 2 pelvic ring disruptions: Should surgeons prioritize the anterior ring?

PURPOSE: Surgical intervention for lateral compression (LC) 1 and 2 pelvic ring fractures is controversial. Posterior ring stabilization remains the most common mode of initial fixation. However, greater mechanical instability is observed in the anterior component of LC pelvic fractures. This study tested whether reduction and percutaneous superior ramus fixation will decrease the instability of LC pelvic fractures on intraoperative fluoroscopic imaging. METHODS: All adult patients (≥ 18 years) presenting with either a Young-Burgess LC1 or LC2 pelvic ring disruption treated operatively with percutaneous anterior followed by posterior fixation by a single surgeon from July 2021 to June 2023 were retrospectively reviewed. Displacement of the anterior ring to intraoperative manual internal rotation stress examination under fluoroscopy was compared before and after anterior pelvic ring reduction and fixation and prior to posterior pelvic ring fixation. Pre- and post-operative visual analog scores (VAS) for pain were also compared. RESULTS: Twenty-one patients with a mean age of 48.7 years were included. Fifteen patients (71.4%) presented with an LC1, and six (28.6%) with an LC2 injury patterns. Anterior pelvic fixation alone provided 7.5mm reduction in mean displacement of the anterior pelvic ring (pre-operative = 9.2 mm vs. post-operative = 1.6 mm, p < 0.001). VAS significantly decreased from 7.2 one-day pre-operatively to 2.2 twenty-four h post-operatively (p < 0.001). CONCLUSIONS: Reduction and fixation of the anterior pelvic ring prior to posterior fixation for LC1 and LC2 pelvic ring disruptions substantially improves mechanical stability on intraoperative stress examination. Combination of percutaneous anterior and posterior fixation significantly decreased VAS above the MCID 24 h after stabilization.

Titanium versus stainless steel alloy bridge plates for distal femur fractures: Does callus form earlier with titanium?

INTRODUCTION: Distal femur fractures account for 3-6% of all femur fractures. Internal fixation of most distal femur fractures with an anatomic lateral locking plate should permit some motion at the metaphyseal portion of the fracture when secondary bone healing is planned by the operating surgeon. While several studies have been performed evaluating union rates for distal femur fractures with stainless steel and titanium plates, the timing of callus formation between stainless steel and titanium implants used as bridge plates for distal femur fractures (AO/OTA 33-A and -C) has been investigated to a lesser extent. We hypothesize that callus will be visualized earlier with post-operative radiographs with titanium versus stainless steel bridge plates. METHODS: We retrospectively reviewed a consecutive cohort of patients over 18 years of age with acute AO/OTA 33-A and 33-C fracture patterns treated with an isolated stainless steel or titanium lateral bridge plate within 4 weeks of injury by a single fellowship-trained orthopedic trauma surgeon from 2011 to 2020 at one academic Level 1 trauma center. An independent, fellowship-trained orthopedic trauma attending surgeon reviewed anterior-posterior (AP) and lateral radiographs from every available post-operative clinic visit and graded them using the Modified Radiographic Score for Tibia (mRUST). RESULTS: Twenty-five subjects were included in the study with 10 with stainless steel and 15 with titanium plates. There were no significant differences in demographics between both groups, including age, sex, BMI, injury classification, open versus closed, mechanism, and laterality. Statistically significant increased mRUST scores, indicating increased callus formation, were seen on 12-week radiographs (8.4 vs. 11.9, p = 0.02) when titanium bridge plates were used. There were no statistically significant differences in mRUST scores at 6 or 24-weeks, but scores in the titanium group were higher in at every timepoint. DISCUSSION: In conclusion, we observed greater callus formation at 12 weeks after internal fixation of 33-A and 33-C distal femur fractures treated with titanium locked lateral distal femoral bridge plates compared to stainless steel plates. Our data suggest that titanium metallurgy may have quicker callus formation compared to stainless steel if an isolated, lateral locked bridge plate is chosen for distal femur fracture fixation.

Subchondral rafting wires reduce tibial plateau fracture subsidence.

PURPOSE: To determine if subchondral rafting wires retained as adjunctive tibial plateau fracture fixation affect postoperative articular subsidence. METHODS: A retrospective cohort study was conducted at one Level 1 trauma center and one academic university hospital. Consecutive adults with closed, displaced OTA/AO 41B/C tibial plateau fractures treated between 2018 and 2023 with open reduction internal fixation were included. Patients who were not ambulatory, with contralateral injuries limiting weight bearing, and without follow-up radiographs of the injured extremity were excluded. The intervention was retention of subchondral rafting wires as definitive fixation. The primary outcome was linear articular surface subsidence between postoperative and follow-up AP knee radiographs. Linear subsidence was compared between groups using Welch's two sample t test. Associations of linear subsidence with patient, injury, and treatment characteristics were assessed by multivariable linear regression. RESULTS: We identified 179 patients of a mean age of 44 ± 14 years, of whom 15 (8.4%) received subchondral rafting wires. Median follow-up was 121 days. No patients who received rafting wires as definitive implants experienced linear subsidence ≥ 2 mm, while 22 patients (13.4%) who did not receive rafting wires experienced linear subsidence ≥ 2 mm (p = 0.130). Subchondral rafting wires were associated with less linear subsidence (0.3 mm [95% confidence interval - 0.3-0.9 mm] vsersus 1.0 mm [- 0.9-2.9 mm], p < 0.001). The depth of linear subsidence was significantly associated on multivariable regression with male sex, depressed plateau area, active smoking, and retained rafting wires. CONCLUSION: Subchondral rafting wires were associated with a small reduction in articular subsidence after internal fixation of tibial plateau fractures. Routine rafting wires may be useful for patients and fractures at high risk of articular subsidence.

Anterior internal versus external fixation of unstable pelvis fractures was not associated with discharge destination, critical care, length of stay, or hospital charges.

PURPOSE: Determine if anterior internal versus supra-acetabular external fixation of unstable pelvic fractures is associated with care needs or discharge. METHODS: A retrospective cohort study was performed at two tertiary trauma referral centers. Adults with unstable pelvis fractures (AO/OTA 61B/61C) who received operative fixation of the anterior and posterior pelvic ring by two orthopedic trauma surgeons from October 2020 to November 2022 were included. The primary outcome was discharge destination. Secondary outcomes included intensive care unit (ICU) or ventilator days, length of stay, and hospital charges. RESULTS: Eighty-three eligible patients were 38.6% female, with a mean age of 47.2 ± 20.3 years and BMI 28.1 ± 6.4 kg/m2. Fifty-nine patients (71.1%) received anterior pelvis internal fixation and 24 (28.9%) received external fixation. External fixation was associated with weight-bearing restrictions (91.7% versus 49.2%, p = 0.01). No differences in demographic, functional status, insurance type, fracture classification, or injury severity measures were observed by treatment. Internal versus external anterior pelvic fixation was not associated with discharge to home (49.2% versus 29.2%, p = 0.10), median ICU days (3.0 [interquartile range (IQR) 7.8 versus 5.5 [IQR 4.3], p = 0.14, ventilator days (0 [IQR 6.0] versus 0 [IQR 2.8], p = 0.51), length of stay (13.0 [IQR 13.0] versus 17.5 (IQR 20.5), p = 0.38), or total hospital charges (US dollars 180,311 [IQR 219,061.75] versus 243,622 [IQR 187,111], p = 0.14). CONCLUSIONS: Anterior internal versus supra-acetabular external fixation of unstable pelvis fractures was not significantly associated with discharge destination, critical care, hospital length of stay, or hospital charges. This sample may be underpowered to detect differences between groups. LEVEL OF EVIDENCE: Therapeutic Level IV.

Waste-Free Fully Electrically Fueled Dissipative Self-Assembly System.

The importance and prevalence of energy-fueled active materials in living systems have inspired the design of synthetic active materials using various fuels. However, several major limitations of current designs remain to be addressed, such as the accumulation of chemical wastes during the process, unsustainable active behavior, and the lack of precise spatiotemporal control. Here, we demonstrate a fully electrically fueled (e-fueled) active self-assembly material that can overcome the aforementioned limitations. Using an electrochemical setup with dual electrocatalysts, the anodic oxidation of one electrocatalyst (ferrocyanide, [Fe(CN)6]4-) creates a positive fuel to activate the self-assembly, while simultaneously, the cathodic reduction of the other electrocatalyst (methyl viologen, [MV]2+) generates a negative fuel triggering fiber disassembly. Due to the fully catalytic nature for the reaction networks, this fully e-fueled active material system does not generate any chemical waste, can sustain active behavior for an extended period when the electrical potential is maintained, and provides spatiotemporal control.

Facile Synthesis of Multifunctional Bioreducible Polymers for mRNA Delivery.

Bioreducible polymeric mRNA carriers are an emerging family of vectors for gene delivery and vaccine development. A few bioreducible systems have been generated through aqueous-phase ring-opening polymerization of lipoic acid derivatives, however this methodology limits hydrophobic group incorporation and functionality into resulting polymers. Herein, a poly(active ester)disulfide polymer is synthesized that can undergo facile aminolysis with amine-containing substrates under stoichiometric control and mild reaction conditions to yield a library of multifunctional polydisulfide polymers. Functionalized polydisulfide polymer species form stable mRNA-polymer nanoparticles for intracellular delivery of mRNAs in vitro. Alkyl-functionalized polydisulfide-RNA nanoparticles demonstrate rapid cellular uptake and excellent biodegradability when delivering EGFP and OVA mRNAs to cells in vitro. This streamlined polydisulfide synthesis provides a new facile methodology for accessing multifunctional bioreducible polymers as biomaterials for RNA delivery and other applications.

A Close Look at Molecular Self-Assembly with the Transmission Electron Microscope.

Molecular self-assembly is pervasive in the formation of living and synthetic materials. Knowledge gained from research into the principles of molecular self-assembly drives innovation in the biological, chemical, and materials sciences. Self-assembly processes span a wide range of temporal and spatial domains and are often unintuitive and complex. Studying such complex processes requires an arsenal of analytical and computational tools. Within this arsenal, the transmission electron microscope stands out for its unique ability to visualize and quantify self-assembly structures and processes. This review describes the contribution that the transmission electron microscope has made to the field of molecular self-assembly. An emphasis is placed on which TEM methods are applicable to different structures and processes and how TEM can be used in combination with other experimental or computational methods. Finally, we provide an outlook on the current challenges to, and opportunities for, increasing the impact that the transmission electron microscope can have on molecular self-assembly.

Early hip survival after open reduction internal fixation of acetabular fracture.

PURPOSE: To estimate survival of acetabular fracture repair by tracking patients across healthcare encounters. We hypothesized that hip survival estimated this way would be lower than reported by single-surgeon or single-center series not capturing censored reoperations. METHODS: Retrospective health insurance administrative database cohort study. All claimed healthcare encounters for employer-sponsored health insurance beneficiaries aged 18-65 years without pre-existing hip pathology with a newly diagnosed acetabular fracture were identified between October 1, 2015, through December 31, 2018. The intervention was open reduction internal fixation of acetabular fracture during index admission. The primary outcome was survival of the acetabular fracture repair to subsequent reoperation by arthroscopy, arthrotomy for drainage of infection, implant removal, revision acetabular fixation, hip arthroplasty, hip resection, or arthrodesis. RESULTS: 38 reoperation procedures on the fractured acetabulum in 852 patients occurred within 2 years (incidence 4.5%). Total hip arthroplasty (2.5%) and revision internal fixation (1.5%) accounted for most early reoperations. Multivariable Cox regression identified an association between reoperation and increasing patient age (hazard ratio = 1.4 per decade, p < 0.01). The prevalence of any mental health condition was 29%. CONCLUSIONS: Non-elderly adults with employer-sponsored insurance who sustain acetabular fractures have a greater burden of mental health disease than similarly insured patients without these injuries. Survival of the native acetabulum after fracture fixation exceeded 95% at 2 years and decreased with increasing patient age. LEVEL OF EVIDENCE: Level III, Prognostic Study.

Obesity classification predicts early complications and mortality after acetabular fracture.

INTRODUCTION: Obesity remains a global epidemic. The effect of obesity on the risk of complications after acetabular fracture is unknown. Here, we evaluate the effect of BMI on early complications and mortality after acetabular fracture. We hypothesize that the risk of inpatient complications and mortality will be greater in patients with high BMI when compared to those with normal BMI. METHODS: Adult patients with acetabular fracture were identified via the Trauma Quality Improvement Program data from 2015 to 2019. The primary outcome was overall complication rate with reference to normal-weight patients (BMI = 25-30 kg/m2). The secondary outcome was rates of death. The association of obesity class on the primary and secondary outcomes was assessed using Bonferroni-corrected multiple logistic regression models considering patient, injury, and treatment covariates. RESULTS: A total of 99,721 patients with acetabular fracture were identified. Class I obesity (BMI = 30-35 kg/m2) was associated with 1.2 greater adjusted relative risk (aRR; 95% confidence interval (CI) 1.1-1.3) of any adverse event, without significant increases in adjusted risk of death. Class II obesity (BMI = 35-40 kg/m2) was associated with aRR = 1.2 (95% CI 1.1-1.3) of any adverse event and aRR = 1.5 (95% CI 1.2-2.0) of death. Class III obesity (BMI ≥ 40 kg/m2) was associated with aRR = 1.3 (95% CI 1.2-1.4) of any adverse event and aRR = 2.3 (95% CI 1.8-2.9) of death. CONCLUSION: Obesity is associated greater risk of adverse events and death following acetabular fracture. Obesity severity classification scales with these risks.

Rising incidence of acute total hip arthroplasty for primary and adjunctive treatment of acetabular fracture in older and middle-aged adults.

BACKGROUND: Acute total hip arthroplasty (THA) may be an alternative or an adjuvant to internal fixation for surgical treatment of acetabular fractures. We investigate recent trends in the operative management of acetabular fractures. We hypothesize that the incidence of acute THA for acetabular fractures has increased over time. METHODS: 4569 middle-aged (45-64 years) and older adults (≥ 65 years) who received acute operative management of an acetabular fracture within 3 weeks of admission between 2010 and 2020 were identified from the United States Nationwide Inpatient Sample database. Treatment was classified as open reduction internal fixation (ORIF), THA, or combined ORIF and THA (ORIF + THA). Patients were stratified by age ≥ 65 years old. Associations between demographic factors and the incidence of each procedure over the study period were modeled using linear regression. RESULTS: The relative incidence of treatments was 80.9% ORIF, 12.1% THA, and 7.0% ORIF + THA. Among patients aged 45-64 years old, THA increased 4.8% [R2 = 0.62; ß1 = 0.6% (95% Confidence Interval (CI) 0.2-0.9%)] and ORIF + THA increased 2.6% [R2 = 0.73; ß1 = 0.3% (95% CI 0.2-0.4%)], while the use of ORIF decreased 7.4% [R2 = 0.75; ß1 = -0.9% (95% CI -1.2 to -0.5%)]. Among patients ≥ 65 years old, THA increased 16.5% [R2 = 0.87; ß1 = 1.7% (95% CI 1.2-2.2%)] and ORIF + THA increased 5.0% [R2 = 0.38, ß1 = 0.6% (95% CI 0.0-1.3%)], while ORIF decreased 21.5% [R2 = 0.75; ß1 = -2.4% (95% CI -3.45 to -1.3%)]. CONCLUSION: The treatment of acetabular fractures with acute THA has increased in the last decade, particularly among older adults.

Underweight patients experience higher inpatient complication and mortality rates following acetabular fracture.

PURPOSE: Underweight patients experience poor outcomes after elective orthopaedic procedures. The effect of underweight body mass index (BMI) on complications after acetabular fracture is not well-described. We evaluate if underweight status is associated with inpatient complications after acetabular fractures. METHODS: Adult patients (≥ 18 years) presenting with acetabular fracture between 2015 and 2019 were identified from Trauma Quality Program data. Adjusted odds (aOR) of any inpatient complication or mortality were compared between patients with underweight BMI (< 18.5 kg/m2) and normal BMI (18.5-25 kg/m2) using multivariable logistic regression and stratifying by age ≥ 65 years. RESULTS: The 1299 underweight patients aged ≥ 65 years compared to 11,629 normal weight patients experienced a 1.2-times and 2.7-times greater aOR of any complication (38.6% vs. 36.6%, p = 0.010) and inpatient mortality (7.9% vs. 4.2%, p < 0.001), respectively. The 1688 underweight patients aged 18-64 years compared to 24,762 normal weight patients experienced a 1.2-times and 1.5-times greater aOR of any inpatient complication (38.9% vs. 34.8%, aOR p = 0.006) and inpatient mortality (4.1% vs. 2.5%, p < 0.001), respectively. CONCLUSION: Underweight adult patients with acetabular fracture are at increased risk for inpatient complications and mortality, particularly those ≥ 65 years old. LEVEL OF EVIDENCE: Prognostic Level III.

Do superficial infections increase the risk of deep infections in tibial plateau and plafond fractures?

PURPOSE: Open reduction internal fixation of tibial plateau and pilon fractures may be complicated by deep surgical site infection requiring operative debridement and antibiotic therapy. The management of superficial surgical site infection is controversial. We sought to determine whether superficial infection is associated with an increased risk of deep infection requiring surgical debridement after fixation of tibial plateau and pilon fractures. METHODS: This is a secondary analysis of data from the VANCO trial, which included 980 adult patients with a tibial plateau or pilon fracture at elevated risk of infection who underwent open reduction internal fixation with plates and screws with or without intrawound vancomycin powder. An association of superficial surgical site infection with deep surgical site infection requiring debridement surgery and antibiotics was explored after matching on risk factors for deep surgical site infection. RESULTS: Of the 980 patients, we observed 30 superficial infections (3.1%) and 76 deep infections (7.8%). Among patients who developed a superficial infection, the unadjusted incidence of developing a deep infection within 90 days was 12.8% (95% confidence interval [CI] 1.3-24.2%). However, after a 3:1 match on infection risk factors, the 90-day marginal probability of a deep surgical site infection after sustaining a superficial infection was 6.0% (95% CI - 6.5-18.5%, p = 0.35). CONCLUSION: Deep infection after superficial infection is uncommon following operative fixation of tibial plateau and pilon fractures. Increased risk of subsequent deep infection attributable to superficial infection was inconclusive in these data. LEVEL OF EVIDENCE: Prognostic Level II.

Striatal Afferent BDNF Is Disrupted by Synucleinopathy and Partially Restored by STN DBS.

Preclinical studies show a link between subthalamic nucleus (STN) deep brain stimulation (DBS) and neuroprotection of nigrostriatal dopamine (DA) neurons, potentially through brain-derived neurotrophic factor (BDNF) signaling. However, the question of whether DBS of the STN can be disease-modifying in Parkinson's disease (PD) remains unanswered. In particular, the impact of STN DBS on α-synuclein (α-syn) aggregation, inclusion-associated neuroinflammation, and BDNF levels has yet to be examined in the context of synucleinopathy. To address this, we examined the effects of STN DBS on BDNF using the α-syn preformed fibril (PFF) model in male rats. While PFF injection resulted in accumulation of phosphorylated α-syn (pSyn) inclusions in the substantia nigra pars compacta (SNpc) and cortical areas, STN DBS did not impact PFF-induced accumulation of pSyn inclusions in the SNpc. In addition, nigral pSyn inclusions were associated with increased microgliosis and astrogliosis; however, the magnitude of these processes was not altered by STN DBS. Total BDNF protein was not impacted by pSyn inclusions, but the normally positive association of nigrostriatal and corticostriatal BDNF was reversed in rats with PFF-induced nigrostriatal and corticostriatal inclusions. Despite this, rats receiving both STN DBS and PFF injection showed increased BDNF protein in the striatum, which partially restored the normal corticostriatal relationship. Our results suggest that pathologic α-syn inclusions disrupt anterograde BDNF transport within nigrostriatal and corticostriatal circuitry. Further, STN DBS has the potential to exert protective effects by modifying the long-term neurodegenerative consequences of synucleinopathy.SIGNIFICANCE STATEMENT An increase in brain-derived neurotrophic factor (BDNF) has been linked to the neuroprotection elicited by subthalamic nucleus (STN) deep brain stimulation (DBS) in neurotoxicant models of Parkinson's disease (PD). However, whether STN DBS can similarly increase BDNF in nigrostriatal and corticostriatal circuitry in the presence of α-synuclein (α-syn) inclusions has not been examined. We examined the impact of STN DBS on rats in which accumulation of α-syn inclusions is induced by injection of α-syn preformed fibrils (PFFs). STN DBS significantly increased striatal BDNF protein in rats seeded with α-syn inclusions and partially restored the normal corticostriatal BDNF relationship. These findings suggest that STN DBS can drive BDNF in the parkinsonian brain and retains the potential for neuroprotection in PD.