Network analysis of S-nitrosylated synaptic proteins demonstrates unique roles in health and disease.

Nitric oxide can covalently modify cysteine thiols on target proteins to alter that protein's function in a process called S-nitrosylation (SNO). S-nitrosylation of synaptic proteins plays an integral part in neurotransmission. Here we review the function of the SNO-proteome at the synapse and whether clusters of SNO-modification may predict synaptic dysfunction associated with disease. We used a systematic search strategy to concatenate SNO-proteomic datasets from normal human or murine brain samples. Identified SNO-modified proteins were then filtered against proteins reported in the Synaptome Database, which provides a detailed and experimentally verified annotation of all known synaptic proteins. Subsequently, we performed an unbiased network analysis of all known SNO-synaptic proteins to identify clusters of SNO proteins commonly involved in biological processes or with known disease associations. The resulting SNO networks were significantly enriched in biological processes related to metabolism, whereas significant gene-disease associations were related to Schizophrenia, Alzheimer's, Parkinson's and Huntington's disease. Guided by an unbiased network analysis, the current review presents a thorough discussion of how clustered changes to the SNO-proteome influence health and disease.

Genetic and pharmacological reduction of CDK14 mitigates synucleinopathy.

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical α-Syn pathology, indicated by reduced numbers of pS129 α-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic α-Syn species. We further validated these findings on pS129 α-Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable in vitro and in vivo. We found that CDK14 inhibition decreases total and pathologically aggregated α-Syn in human neurons, in PFF-challenged rat neurons and in the brains of α-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy.

Hip Fracture Repair by the Post-Call Surgeon: A Multicenter Retrospective Review.

INTRODUCTION: The purpose of this study was to evaluate surgeons' ability to perform or supervise a standard operation with agreed-upon radiologic parameters after being on call. METHODS: We reviewed a consecutive series of patients with intertrochanteric hip fractures treated with a fixed angle device at 9 centers and compared corrected tip-apex distance and reduction quality for post-call surgeons versus those who were not. Subgroup analyses included surgeons who operated the night before versus not and attending-only versus resident involved cases. Secondary outcomes included union and perioperative complications. RESULTS: One thousand seven hundred fourteen patients were of average age 77 years. Post-call surgeons treated 823 patients and control surgeons treated 891. Surgical corrected tip-apex distance did not differ between groups: on-call 18 mm versus control 18 mm (P = 0.59). The Garden indices were 160° on the AP and 179° on the lateral in both groups. In 66 cases performed by surgeons who operated the night before, the TAD was 17 mm. No difference was noted in corrected tip-apex distance with and without resident involvement (P = 0.101). No difference was observed in pooled fracture-related complications (P = 0.23). CONCLUSION: Post-call surgeons demonstrated no difference in quality and no increase in complications when performing hip fracture repair the next day compared with surgeons who were not on call.

Effect of Antibiotic Administration Before Joint Aspiration on Synovial Fluid White Blood Cell Count in Native Joint Septic Arthritis.

Background: This study was performed to assess the impact of preaspiration antibiotics on synovial fluid analysis and timing of operative treatment in native-joint septic arthritis. Methods: We performed a retrospective record review of adult patients from an urban level 1 trauma center with native joint septic arthritis in 2015-2019, identified by means of codes from the International Classification of Diseases (Ninth Revision and Tenth Revision). Univariate and multivariate analyses were performed to determine whether antibiotics were associated with lower synovial fluid white blood cell counts (WBCs), the percentage of polymorphonuclear neutrophil (PMNs), and rate of culture positivity. Secondary analysis included time elapsed from aspiration to surgery. Results: Of the 126 patients with septic joints included, nearly two-thirds (n = 80 [63.5%]) received antibiotics before joint aspiration. The synovial fluid WBC count, percentage of PMNs, and rate of culture positivity were significantly lower in patients who received preaspiration antibiotics than in those who did not (mean WBC count, 51 379.1/µL [standard deviation, 52 576.3/µL] vs 92 162.7/µL [59 330.6/µL], respectively [P < .001]; PMN percentage, 83.6% [20.5%] vs 91.9% [6.0%; P = .01]; and culture positivity, 32.5% vs 59.1% [P = .008]). Multivariable analyses revealed that these associations remained after controlling for potential confounders (change in PMNs, -42 784.60/µL [95% confidence interval, -65 355/µL to -20 213.90/µL [P < .001]; change in PMNs, -7.8% [-13.7% to -1.8%] [P = .01]; odds ratio, 0.39 [.18-.87; P = .02). Patients with a synovial fluid WBC count ≤50 000/µL experienced significant delay in time from joint aspiration to operative intervention (mean [standard deviation], 10.5 [11.3] vs 17.9 [17.2] hours; P = .02). Conclusions: The administration of antibiotics before joint aspiration for suspected septic arthritis appears to decrease the synovial fluid WBC count, the percentage of PMNs, and the rate of culture positivity. Efforts to limit antibiotic administration before joint aspiration are important to minimize diagnostic dilemmas and circumvent treatment delays.

Incidence of Complications and Revision Surgery After High Tibial Osteotomy: A Systematic Review.

BACKGROUND: High tibial osteotomy (HTO) is a well-recognized procedure for its effectiveness in treating symptomatic early knee arthritis and malalignment. Although there are numerous systematic reviews evaluating the management and outcomes after HTO, there are few investigations on complications of this procedure. PURPOSE: To systematically review the literature to determine the incidence of intraoperative and postoperative complications associated with medial opening wedge and lateral closing wedge HTOs. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: The Cochrane Database of Systematic Reviews, PubMed, Embase, and MEDLINE databases were queried for studies reporting complications associated with HTO with or without concomitant procedures. Data including patient characteristics, procedure type, concomitant procedures, follow-up time, and postoperative imaging were extracted. Rates of intra- and postoperative complications, reoperations, and conversion to arthroplasty were recorded. RESULTS: A total of 71 studies were included for analysis, comprising 7836 patients. The overall intraoperative complication rate during HTO was 5.5% (range, 0%-29.3%), and the overall postoperative complication rate was 6.9% (range, 0%-26.6%). The most common intraoperative complication was lateral hinge fracture (incidence, 9.1%; range, 0%-30.4%) in medially based HTOs and peroneal nerve injury in laterally based HTOs (incidence, 3.2%; range, 0%-8.7%). The overall incidence of neurovascular injury after medially or laterally based HTOs was 1.1% (range, 0%-18.9%). The most common postoperative complication was superficial infection (incidence, 2.2%; range, 0%-13%). Of the included studies, 62 included postoperative radiographic analysis, and among those, the incidence of nonunion was 1.9% (range, 0%-15.5%), loss of correction was 1.2% (range, 0%-34.3%), and implant failure was 1.0% (range, 0%-10.2%). Among studies reporting revision surgeries, the overall reoperation rate was 15.5% (range, 0%-70.7%), with the most common type of reoperation being hardware removal (incidence, 10.0%; range, 0%-60%). CONCLUSION: Intraoperatively, medially based HTOs are associated with a 1 in 11 risk of lateral hinge fracture and laterally based HTOs with a 1 in 30 risk of peroneal nerve injury. Postoperative complication rates in the range of 10% to 15% can be expected, including infection (2.9%), loss of correction (1.2%), and nonunion (1.9%). Patients should also be counseled that the reoperation rate is approximately 15%, with hardware removal being the most common procedure.

Accurate Computation of Thermodynamic Activation Parameters in the Chorismate Mutase Reaction from Empirical Valence Bond Simulations.

Chorismate mutase (CM) enzymes have long served as model systems for benchmarking new methods and tools in computational chemistry. Despite the enzymes' prominence in the literature, the extent of the roles that activation enthalpy and entropy play in catalyzing the conversion of chorismate to prephenate is still subject to debate. Knowledge of these parameters is a key piece in fully understanding the mechanism of chorismate mutases. Within this study, we utilize EVB/MD free energy perturbation calculations at a range of temperatures, allowing us to extract activation enthalpies and entropies from an Arrhenius plot of activation free energies of the reaction catalyzed by a monofunctional Bacillus subtilis CM and the promiscuous enzyme isochorismate pyruvate lyase of Pseudomonas aeruginosa. In comparison to the uncatalyzed reaction, our results show that both enzyme-catalyzed reactions exhibit a substantial reduction in activation enthalpy, while the effect on activation entropy is relatively minor, demonstrating that enzyme-catalyzed CM reactions are enthalpically driven. Furthermore, we observe that the monofunctional CM from B. subtilis more efficiently catalyzes this reaction than its promiscuous counterpart. This is supported by a structural analysis of the reaction pathway at the transition state, from which we identified key residues explaining the enthalpically driven nature of the reactions and also the difference in efficiencies between the two enzymes.

State-level policies and reunification: A multi-level survival analysis.

BACKGROUND: A growing body of research has focused on the relationships of policies and other macro factors and child welfare outcomes. However, to date, few studies have examined state child welfare policies and reunification, despite reunification being the priority case goal among children in foster care. OBJECTIVE: This study examined the relationship between state child welfare policies and other macro factors and reunification, while controlling for child factors. PARTICIPANTS AND SETTING: Data came from the 2016-2019 Adoption and Foster Care Analysis Reporting System (AFCARS), which contains case-level information on all children in foster care during each fiscal year. METHODS: We conducted a series of multi-level survival analyses to observe the fixed effects of state-level factors and child-level factors on time to reunification among children who entered foster care in 2016. RESULTS: In the unadjusted model, children in states with Title IV-E stipend programs for caseworkers had higher hazards of reunification (HR = 1.21, 95 % CI = 1.01-1.44) as did children in states with statewide in-home post-reunification services (HR = 1.63, 95 % CI = 1.16-2.28). Children in states that required a master's degree for caseworkers had lower hazards of reunification (HR = 0.72, 95 % CI = 0.59-0.95). CONCLUSIONS: Findings from this study highlight the importance of considering state policies and their impact on reunification. Implications for policy, practice, and research are explored.

Predictors of Hardware Removal in Orthopaedic Trauma Patients Undergoing Syndesmotic Ankle Fixation With Screws.

Background: Indications for removal of syndesmotic screws are not fully elucidated. This study aimed to determine factors related to elective syndesmotic screw removal. Methods: Patients who underwent fixation of ankle syndesmotic injuries were included. Screw removal was offered after a minimum of 12 weeks after surgery for pain, stiffness or patient desire to remove painful or broken hardware. Patient demographics, surgical data, distance of the syndesmotic screw from the joint, location of the screw at the physeal scar, and number of syndesmotic screws placed were collected for all patients. Bivariate and multivariate analyses were performed to determine the relationship between patient characteristics and screw removal and independent predictors of hardware removal. Results: Of 160 patients, 60 patients (38%) with an average age of 36.1 (range: 18-84) years underwent elective syndesmotic screw removal at a mean of 7 (range, 3-47) months after initial fixation. The most common reason for screw removal (50/60 patients) was ankle stiffness and pain (83%). Patients who underwent screw removal were more likely to be younger (36.1 years ± 13.0 vs 46.6 years ± 18.2, P < .001) and have a lower ASA score (2 ± 0.8 vs 2.1 ± 0.7, P = .003) by bivariate analysis. Of patients who underwent screw removal, 21.7% (13/60) had a broken screw at the time of removal. Whether the screw was placed at the physeal scar was not significantly associated with patient decision for hardware removal (P = .80). Conclusion: Younger and healthier patients were more likely to undergo elective removal of syndesmotic hardware. Screw distance from joint and screw placement at the physeal scar were not significantly associated with hardware removal. Level of Evidence: Level III, retrospective cohort study.

Heterotopic Ossification Remodeling After Acetabular Surgery: A Natural History Case Report.

CASE: A 30-year-old woman presented with a transverse plus posterior wall acetabular fracture and underwent operative fixation through a Kocher-Langenbeck approach. Shared decision was made for no heterotopic ossification (HO) prophylaxis. The patient developed symptomatic HO and was scheduled for resection, which was delayed because of the pandemic. She returned with interval remodeling of HO and symptom resolution. No surgery was required. CONCLUSION: HO is a common complication after acetabular injury. Resection is the treatment of choice for symptomatic HO. We are not aware of other reports of spontaneous remodeling of symptomatic HO such that it no longer required surgery.

Primary cutaneous marginal zone lymphoma presenting with secondary chilblains of the toes.

Cutaneous lymphoproliferative disorders include cutaneous manifestations of systemic B-cell or T-cell lymphoma and primary cutaneous lymphomas. Primary cutaneous B-cell lymphomas are subcategorised into four groups: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle centre lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg-type and EBV-positive mucocutaneous tumour. Each of these cutaneous lymphoproliferative disorders has unique clinical and pathological features necessitating biopsy and staging to establish proper treatment. We present a case of PCMZL manifesting as secondary chilblains of the toes that was diagnosed with punch skin biopsy. The patient's chilblains resolved with rituximab. This case underscores the importance of considering PCMZL and other cutaneous lymphoproliferative disorders in patients with dermatological manifestations and wounds refractory to first-line treatment.

How to place a cephalomedullary screw when visualization is obscured by the jig in peritrochanteric hip fractures using "peek radiographs."

Lag screw positioning can be difficult to discern intraoperatively on lateral fluoroscopic imaging during intramedullary fixation of proximal femur fractures in some nailing systems due to the drill guide handle obstructing the view. We have described a method of obtaining non-obstructed lateral-oblique "peek" views that reliably assist in obtaining adequate tip-apex distance (TAD) measurements when using intramedullary fixation for these fractures. The purpose of this study was (1) to describe an intraoperative radiographic technique to obtain non-obscured views for appropriate center-center placement of the lag screw(s) within the femoral head during jig-aided cephalomedullary nailing of peritrochanteric hip fractures and (2) to present a case series detailing the radiographic results using this technique. This clinical series of sixty-five patients with intertrochanteric or subtrochanteric proximal femur fractures stabilized with a cephalomedullary nail had an average TAD of 15.1 ± 3.3mm (range: 9.4mm-26.2mm). This suggests that our technical trick of obtaining "peek" radiographs intraoperatively may aid in a precise lag-screw placement.

Is Patellar Instability a Contraindication to Semiextended Tibial Nailing?: A Case Report.

CASE: We report a 40-year-old woman with undiagnosed patellofemoral instability that worsened 8 months after intramedullary nailing of a distal left tibia fracture in the semiextended position through a partial medial parapatellar approach. Patella stability and asymptomatic knee function were restored after IM nail removal, medial patellofemoral ligament repair, and left tibial tubercle transposition. CONCLUSION: The optimal surgical approach for tibial IM nailing in patients with chronic patellar instability has not been described. Clinicians should be cognizant of the potential for worsening patellofemoral instability in these patients when using the medial parapatellar approach in the semiextended position.

Not All Proximal Humerus Fractures Do Well Without Surgery: Anterior Translation Predicts the Need for Surgery.

OBJECTIVES: To evaluate the effect of translation on a large series of low-energy proximal humerus fractures initially treated nonoperatively. DESIGN: Retrospective multicenter analysis. SETTING: Five level-one trauma centers. PATIENTS/PARTICIPANTS: Two hundred ten patients (152 F; 58 M), average age 64, with 112 left- and 98 right-sided low-energy proximal humerus fractures (OTA/AO 11-A-C). INTERVENTION: All patients were initially treated nonoperatively and were followed for an average of 231 days. Radiographic translation in the sagittal and coronal planes was measured. Patients with anterior translation were compared with those with posterior or no translation. Patients with ≥80% anterior humeral translation were compared with those with <80% anterior translation, including those with no or posterior translation. MAIN OUTCOMES: The primary outcome was failure of nonoperative treatment resulting in surgery and the secondary outcome was symptomatic malunion. RESULTS: Nine patients (4%) had surgery, 8 for nonunion and 1 for malunion. All 9 patients (100%) had anterior translation. Anterior translation compared with posterior or no sagittal plane translation was associated with failure of nonoperative management requiring surgery ( P = 0.012). In addition, of those with anterior translation, having ≥80% anterior translation compared with <80% was also associated with surgery ( P = 0.001). Finally, 26 patients were diagnosed with symptomatic malunion, of whom translation was anterior in 24 and posterior in 2 ( P = 0.0001). CONCLUSIONS: In a multicenter series of proximal humerus fractures, anterior translation of >80% was associated with failure of nonoperative care resulting in nonunion, symptomatic malunion, and potential surgery. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Impingement and perforation of the anterior femoral cortex in cephalomedullary nailing: Systematic review and surgical techniques.

BACKGROUND: Anterior femoral cortical impingement and perforation are known risks of cephalomedullary nailing. The incidence of and risk factors for these findings have not been fully established in the literature. The purpose of this review was to answer: (1) What is the incidence of anterior femoral cortical impingement and perforation associated with cephalomedullary nailing of proximal femur fractures? (2) How does incidence vary by nail radius of curvature (ROC)? (3) What populations are at increased risk of impingement and perforation? (4) What surgical techniques prevent their occurrence? HYPOTHESIS: Our hypothesis was that impingement would be a relatively common finding following cephalomedullary nailing, and perforation would be much less frequent but still an appreciable risk. Secondarily, nails with a larger ROC would have a higher rate of impingement. PATIENTS AND METHODS: In this systematic review, PubMed, MEDLINE, and Cochrane databases were searched for articles from 1990-2020 written in English using the terms "cephalomedullary nail" or "femoral nail" and "perforation" or "impingement", and similar words. Inclusion criteria were studies discussing the complication of anterior femoral cortical impingement or perforation associated with the use of a cephalomedullary nail. Fourteen studies met inclusion criteria. Rates of anterior femoral cortical impingement or perforation, patient demographics, nail type, and ROC were extracted. Surgical techniques to prevent perforation were qualitatively reviewed. RESULTS: The rate of anterior cortical impingement with long cephalomedullary nails was 17.2% (192/1117 patients) and with short nails was 29.2% (176/602). The rate of anterior cortical perforation with long nails was 1.0% (11/1116) and with short nails was 0% (0/234). Long nails with ROC>150cm showed an impingement rate of 10.9% (62/567) and perforation rate of 1.1% (7/617 patients). Nails with ROC 150cm or 100cm had an impingement rate of 1.1% (1/93) and perforation rate of 0% (0/93). DISCUSSION: Impingement and perforation of the anterior femoral cortex during cephalomedullary nailing are appreciable risks that surgeons should anticipate and avoid, especially in certain populations and with nails with larger ROC. Surgeons may consider use of long nails with ROC 150cm and below, given a nearly 10-fold lower incidence of impingement and no reported perforations. LEVEL OF EVIDENCE: Therapeutic, level IV.

Is fixation of the medial malleolus necessary in unstable ankle fractures?

INTRODUCTION: It is unclear whether the medial malleolus in unstable bi- and tri- malleolar ankle fractures without medial talar displacement should be addressed surgically. This study reviews a fixation protocol for the medial malleolar component of unstable bi- or tri- malleolar ankle fractures. MATERIALS AND METHODS: Two hundred fifty-seven patients who sustained bi- (AO/OTA 44-B2) or tri- (AO/OTA 44-B3) malleolar ankle fractures between January 2005 and August 2019 at two Level 1 trauma centers were retrospectively identified. Medial malleolar fractures were defined as anterior, supra or intercollicular fractures based on the exit of the posterior fracture line. Fixation of the medial malleolar component was performed based on surgical algorithm. Only large or significantly displaced medial malleolar fractures were fixed if the soft tissues were amenable. Primary outcome measure was the presence of medial-sided ankle pain after operative or non-operative treatment of the medial malleolar fracture after a minimum follow up of 6 months. Presence of pain was defined by a pain score of 3 or higher on a 10-point VAS pain score at the site of the medial malleolar fracture. RESULTS: Significantly more patients in the supracollicular group reported the presence of pain when this type was not fixed versus fixed (28 vs 14%, p = 0.0094). Significantly more patients in the anterior collicular subgroup reported the presence of pain when this type was fixed versus not fixed (40 vs 10%, p = 0.0438). There was no difference in the number of patients reporting pain in the intercollicular group when comparing those who were fixed versus not fixed, (21 vs 22%, p = 1.000). CONCLUSIONS: When examining post-operative pain, not all medial malleolar fractures require fixation when appropriately selected based on fracture pattern. Only 10% of patients with anterior collicular fractures reported pain after non operative management. Unsurprisingly, more patients in the supracollicular fractures reported pain without surgery compared to with surgery. Fracture pattern should be considered in the treatment algorithm for the medial malleolar component in bi- and tri- malleolar fractures.

Open lower extremity fractures in the geriatric population.

INTRODUCTION: Open fractures in the elderly are distinct compared to younger populations. The purpose of this study is to follow a series of open fractures of the lower extremity in the geriatric population to better prognosticate outcomes. METHODS: We performed a retrospective chart review of patients over the age of 65 years old who were treated for an open, lower extremity fracture across two level I trauma medical systems. Patients were included if they had documented wound healing problems in the postoperative period, or 6 months of follow-up, or if they had a definitive radiographic outcome. Sixty-four patients were included of an average age of 76.23, of whom 73.4% were female. RESULTS: The fracture types were midshaft femur in 3, distal femur in 9, patella in 2, proximal tibia in 3, proximal fibula in 1, midshaft tibia in 14, distil tibia in 8, ankle in 23, and talar neck/calcaneus in 1. Forty-two fractures were the result of low energy mechanism and 22 fractures were from high energy mechanism. Fourteen fractures were type 1, 32 were type 2, 11 were type 3A, 6 were type 3B, and 1 was type 3C. At final follow-up, 13 wounds were well healed, 39 wounds were healed following a delay of more than 6 weeks to achieve healing, 3 were infected, 3 had been treated with amputation, 2 had chronic ulceration, 2 with active draining, and 2 had draining sinuses. DISCUSSION: Open lower extremity fractures are serious injuries with high rates of morbidity. Such risks are even higher in the geriatric population, particularly with regard to wound healing. This study provides important prognostic information in counseling geriatric patient with an open lower extremity fracture, as well as informs treatment in terms of wound surveillance and care in the postoperative period.

Hyoid Suspension With UPPP for the Treatment of Obstructive Sleep Apnea.

This retrospective evaluation of surgical outcomes for hyomandibular suspension when performed with uvulopalatopharyngoplasty (UPPP) for the treatment of obstructive sleep apnea (OSA). Thirty-nine patients with moderate-to-severe OSA were treated with hyoid myotomy and suspension and uvulopalatopharyngoplasty. Patients underwent hyoid advancement and suspension to the mandible (Encore System) with either staged or concurrent UPPP. The primary outcome was a successful surgical result, defined as an apnea hypopnea index (AHI) lower than 20, and a 50% or greater decline in AHI on postoperative polysomnography. Successful surgical results were achieved in 30 (76.9%) out of 39 patients. The mean preoperative AHI improved 69.2% from 49.9 ± 25.6 to 15.4 ± 14.9 (P < .001) postoperatively. All patients reported clinical improvement of symptoms. There were 4 wound complications and one infection requiring removal of hardware. For patients with multilevel obstructive sleep apnea, hyoid advancement and suspension to the mandible appears efficacious when performed in conjunction with uvulopalatopharyngoplasty.

Intracellular Accumulation of α-Synuclein Aggregates Promotes S-Nitrosylation of MAP1A Leading to Decreased NMDAR-Evoked Calcium Influx and Loss of Mature Synaptic Spines.

Cortical synucleinopathies, including dementia with Lewy bodies and Parkinson's disease dementia, collectively known as Lewy body dementia, are characterized by the aberrant aggregation of misfolded α-synuclein (α-syn) protein into large inclusions in cortical tissue, leading to impairments in proteostasis and synaptic connectivity and eventually resulting in neurodegeneration. Here, we show that male and female rat cortical neurons exposed to exogenous α-syn preformed fibrils accumulate large, detergent-insoluble, PS129-labeled deposits at synaptic terminals. Live-cell imaging of calcium dynamics coupled with assessment of network activity reveals that aberrant intracellular accumulation of α-syn inhibits synaptic response to glutamate through NMDARs, although deficits manifest slowly over a 7 d period. Impairments in NMDAR activity temporally correlated with increased nitric oxide synthesis and S-nitrosylation of the dendritic scaffold protein, microtubule-associated protein 1A. Inhibition of nitric oxide synthesis via the nitric oxide synthase inhibitor l-NG-nitroarginine methyl ester blocked microtubule-associated protein 1A S-nitrosylation and normalized NMDAR-dependent inward calcium transients and overall network activity. Collectively, these data suggest that loss of synaptic function in Lewy body dementia may result from synucleinopathy-evoked nitrosative stress and subsequent NMDAR dysfunction.SIGNIFICANCE STATEMENT This work shows the importance of the redox state of microtubule-associated protein 1A in the maintenance of synaptic function through regulation of NMDAR. We show that α-syn preformed fibrils promote nitric oxide synthesis, which triggers S-nitrosylation of microtubule-associated protein 1A, leading to impairment of NMDAR-dependent glutamate responses. This offers insight into the mechanism of synaptic dysfunction in Lewy body dementia.

Democratization of terrorism: an analysis of vehicle-based terrorist events.

Objectives: The COVID-19 pandemic inspired social changes that promote outdoor activities including eating at restaurants, which may linger in a world hyperfocused on disease transmission prevention, increasing the vulnerabilities to vehicle-based terrorism. Vehicle ramming attacks started to transition from a relatively rare method of attack to one of the most lethal forms of terrorism in Western countries just prior to the emergence of SARS-CoV-2. This study aims to provide a historical analysis of the terrorism-based attacks using vehicles between 1970 and 2019. Methods: This study uses the methodology suggested by Tin et al in which the Global Terrorism Database hosted by the National Consortium for the Study of Terrorism and Responses to Terrorism was searched retrospectively for data. Data was collected from the database using the internal search function for terror events between January 1, 1970 and December 31, 2019 which used a vehicle as a means of attack. Results: There were 257 recorded terror attacks that involved some type of vehicle between 1970 and 2019. The attacks resulted in 808 fatalities and 1715 injuries when excluding the September 11 attacks. 76 events occurred at the West Bank and Gaza Strip, 25 in the USA, 16 in Israel, and 14 in the UK. Of the 257 terror incidents, 71% (183) occurred within the last 6-year span of inquiry. Conclusion: By 2016, vehicle attacks were the most lethal form of attack comprising just over half of all terrorism-related deaths in that year. Large gatherings such as festivals, sporting events, and now outdoor seating at restaurants, leave a number of people highly vulnerable to a vehicle ramming attacks depending on established countermeasures. The increased prevalence of outdoor activities and gatherings in a post-COVID-19 world will further expose large numbers of people to the potential vulnerabilities of vehicle-based terrorism. The scale of the casualties from a vehicle-based terror attack can overwhelm traditional resources and strain the abilities of the healthcare sector. Counterterrorism and disaster medicine specialists are crucial players in educating first responders and emergency medicine providers, allowing them to adequately prepare for an evolving threat in a world devastated by COVID-19. Level of evidence: VI.