Computer-Aided Design and Biological Evaluation of Diazaspirocyclic D4R Antagonists.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction. Current treatments are primarily centered around enhancing dopamine signaling or providing dopamine replacement therapy and face limitations such as reduced efficacy over time and adverse side effects. To address these challenges, we identified selective dopamine receptor subtype 4 (D4R) antagonists not previously reported as potential adjuvants for PD management. In this study, a library screening and artificial neural network quantitative structure-activity relationship (QSAR) modeling with experimentally driven library design resulted in a class of spirocyclic compounds to identify candidate D4R antagonists. However, developing selective D4R antagonists suitable for clinical translation remains a challenge.

Patients undergoing reverse total shoulder arthroplasty have less pain and require fewer opioid pain medications compared to anatomic total shoulder arthroplasty in the early postoperative period: a retrospective review.

BACKGROUND: Recovery after anatomic total shoulder arthroplasty (aTSA) and reverse total shoulder arthroplasty (rTSA) has many similarities; however, recently surgeons have suggested patients undergoing rTSA have a less difficult postoperative course with less pain compared with aTSA patients. Given the heightened awareness to postoperative pain control and opioid consumption, as well as the expanding indications for rTSA, we sought to determine the differences in pain and opioid consumption between aTSA and rTSA patients in a 12-week postoperative period. METHODS: A retrospective chart review was performed to identify all patients who underwent a primary aTSA or rTSA from January 2013 to April 2018 at a single institution. Patients with recorded visual analog scale (VAS) and American Shoulder and Elbow Surgeons scores were included for analysis. Revision arthroplasties were excluded. VAS scores were recorded preoperatively and at standard 2-week, 6-week, and 12-week postoperative time points. P values < .05 were considered statistically significant, except where Bonferroni corrections were applied. RESULTS: A total of 690 patients underwent TSA (278 aTSA, 412 rTSA). Preoperatively, aTSA and rTSA patient groups had similar VAS scores (6 vs. 6, P = .38). Postoperatively, the aTSA group had a higher VAS at the 6-week visit, compared with rTSA patients (2.8 vs. 2.2, P = .003). aTSA patients remained on opioids at a higher rate at the 2-week (62.4% vs. 45.6%, P ≤ .001) time period. aTSA patients needed more opioid prescription refills before the 2-week (61.7% vs. 45.5%, P ≤ .001) and 6-week (40.4% vs. 30.7%, P = .01) follow-up visits. CONCLUSIONS: Despite similar preoperative VAS and rates of preoperative opioid use, aTSA patients required more opioid medication refills and remained on opioids for a longer duration in the early postoperative period to achieve similar postoperative pain control as indicated by similar VAS. This study suggests that the recovery from rTSA is less difficult compared with aTSA as indicated by VAS and opioid consumption.

Hip Arthroplasty Femoral Stem Designs and Their Association With Early Postoperative Periprosthetic Femoral Fractures.

BACKGROUND: Periprosthetic femoral fractures (PFFs) in total hip arthroplasty (THA), especially those in contact with the diaphyseal stem, carry high morbidity. This study evaluated how stem design influences the risk of early Vancouver B PFF or other PFF requiring operative intervention after THA. METHODS: A multicenter, retrospective study of 3,433 primary cementless THAs performed from 2014 to 2021 included 2,302 single-taper (micro M/L [n = 1,169]; M/L [n = 1,133]) and 1,131 double-taper (fit-and-fill [n = 420]; compaction-collared [n = 711]) stems. Mean follow-up was 2.2 years (range, 0.3 to 6.5 years). Primary outcomes were Vancouver B and surgically treated postoperative PFFs among differing femoral stems. Secondary outcomes included rates of intraoperative and postoperative Vancouver A and C PFFs. RESULTS: Forty five postoperative PFFs (1.3%) occurred within 8.8 weeks (median), 25 of which were Vancouver B (0.7%) and 20 total PFFs that required operative intervention (0.6%). Compaction-collared stems had a decreased risk of Vancouver B (hazard ratio 0.18, 95% confidence interval: 0.03-0.97 P = .044) and any surgically treated PFF (hazard ratio 0.10, 95% confidence interval: 0.01-0.95; P = .037). Intraoperative PFFs were most common with fit-and-fill stems (3.6%, P < .001) and Vancouver A with compaction-collared stems (1.8%, P < .001). The cohort with PFF had a higher Charlson comorbidity index (P = .004), more women (P = .001), more Dorr A or C femora (P = .013), and more posterior or lateral surgical approaches compared to those without PFF (P ≤ .001). CONCLUSION: After controlling for confounding variables, compaction-collared stems had a significantly lower risk of postoperative Vancouver B and PFF requiring operative treatment than single-taper and double-taper stems.

Opioid-sparing pain management protocol after shoulder arthroplasty results in less opioid consumption and higher satisfaction: a prospective, randomized controlled trial.

BACKGROUND: The opioid epidemic has become a central focus in health care. In an effort to reduce opioid use, orthopedic surgeons use multimodal strategies to control postoperative pain. However, no clear consensus exists on ideal pain management strategies after shoulder arthroplasty, and most protocols are opioid-driven. This study sought to determine if patients undergoing shoulder arthroplasty using a postoperative opioid-sparing pain-control regimen would have equivalent pain scores and satisfaction as patients using a traditional opioid-based regimen. METHODS: Patients undergoing primary anatomic or reverse total shoulder arthroplasty were prospectively enrolled and randomized into an opioid-sparing (OS) or a traditional opioid-based (OB) postoperative pain protocol. Both groups received opioid education, periarticular injection with liposomal bupivacaine, and preoperative and postoperative multimodal management (acetaminophen, celecoxib, and gabapentin). The OB group was discharged with 40 oxycodone tablets and standard icing, whereas the OS group received ketorolac during admission, continuous cryotherapy, and discharged with 10 oxycodone tablets for rescue. Patients were queried regarding levels of pain and opioid consumption at days 1-7 and at 2, 6, and 12 weeks postoperatively. Patient satisfaction was recorded at 1, 2, 6, and 12 weeks. Range of motion (ROM), American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), and Single Assessment Numerical Evaluation (SANE) scores were assessed preoperatively and at 12 weeks postoperatively. Complications, readmissions, and reoperations were recorded. RESULTS: In 78 patients, no difference in VAS pain scores were seen at any time between groups. The OS group consumed less oral morphine equivalents (OME) from inpatient hospitalization to 12 weeks postoperatively (P < .05). Total OME consumption was reduced by 213% for the OS vs. the OB group (112 vs. 239; P < .0001). The OS group consumed fewer opioid pills at all time points (P < .05). A 395% reduction in number of opioid pills consumed in the first 12 weeks postoperatively was seen in the OS vs. the OB group (4.3 vs. 17.0; P < .0001). Significantly more patients in the OS group discontinued opioids by 2 weeks postoperatively (86.1% vs. 58.5%; P = .011), and 94.4% in the OS group discontinued opioids by 6 weeks postoperatively. The OS group was more satisfied with pain management at 1 and 6 weeks (P = .05). No difference in ROM, ASES or SANE scores, complications, readmissions, or reoperations were seen between groups. CONCLUSIONS: This study demonstrated a nearly 4-fold reduction in opioid pain pill consumption and earlier cessation of opioids with an OS pain management protocol. Patients also reported higher satisfaction with this pain management strategy.

Selective demethylation of O-aryl glycosides by iridium-catalyzed hydrosilylation.

The cleavage of alkyl ethers by hydrosilylation is a powerful synthetic tool for the generation of silyl ethers. Previous attempts to apply this transformation to carbohydrate derivatives have been constrained by poor selectivity and preferential reduction of the anomeric position. O-Aryl glycosides are found to be stable under iridium- and borane-catalyzed hydrosilylation conditions, allowing for alkyl ether cleavage without loss of anomeric functionality. A cationic bis(phosphine)iridium complex catalyzes the selective 3-demethylation of a variety of 2,3,4-tri-O-methyl pyranoses, offering a unique approach to 3-hydroxy or 3-acetyl 2,4-di-O-methylpyranoses.

Selective alkyl ether cleavage by cationic bis(phosphine)iridium complexes.

Catalysts capable of heterolytic silane activation have been successfully applied to the conversion of alkyl ethers to silyl ethers via C-O bond cleavage. The previously-reported cationic pincer-supported iridium complex for this transformation suffers from poor selectivity with regard to monodealkylation of substrate ethers. We demonstrate that a simple non-pincer iridium complex offers improved selectivity and is capable of benzylic ether cleavage in the presence of reductively-labile alkyl and aryl halide functionality. Preliminary mechanistic experiments suggest a neutral tetrahydridosilyliridium resting state which is consistent with previous mechanistic hypotheses. These experiments suggest that a pincer ligand framework is not required for activity in ether cleavage reactions and that simple cationic bis(phosphine)iridium complexes may offer improved selectivity profiles for applications to more-complex substrate molecules.

Data Sharing in Neurosurgery and Neurology Journals.

In this era of high health care cost and limited research resources, open access to de-identified clinical research study data may promote increased scientific transparency and rigor, allow for the combination and re-analysis of similar data sets, and decrease un-necessary replication of unpublished negative studies. Driven by expanded computing capabilities, advocacy for data sharing to maximize research value is growing in both translational and clinical research communities. The focus of this study is to report on the current status of publicly available research data from studies published in the top 40 neurology and neurosurgery clinical research journals by impact factor. The top journals were carefully reviewed for data sharing policies. Of the journals with data sharing policies, the 10 most current original research papers from December 2015 - February 2016 were reviewed for data sharing statements and data availability. A data sharing policy existed for 48% (19/40) of the 40 journals investigated. Of the 19 journals with an existing data sharing policy, 58% (11/19) of the policies stated that data should be made available to interested parties upon request and 21% (4/19) of these journals encouraged authors to provide a data sharing statement in the article of what data would be available upon request. Of the 190 articles reviewed for data availability, 21% (40/190) of these articles included some source data in the results, figures, or supplementary sections. This evaluation highlights opportunities for neurology and neurosurgery investigators and journals to improve access to study data and even publish the data prospectively for the betterment of clinical outcome analysis and patient care.