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Purpose: Early onset scoliosis (EOS) patient diversity makes outcome prediction challenging. Machine learning offers an innovative approach to analyze patient data and predict results, including LOS in pediatric spinal deformity surgery., Methods: Children under 10 with EOS were chosen from the American College of Surgeon's NSQIP database. Extended LOS, defined as over 5 days, was predicted using feature selection and machine learning in Python. The best model, determined by the area under the curve (AUC), was optimized and used to create a risk calculator for prolonged LOS., Results: The study included 1587 patients, mostly young (average age: 6.94 ± 2.58 years), with 33.1% experiencing prolonged LOS (n = 526). Most patients were female (59.2%, n = 940), with an average BMI of 17.0 ± 8.7. Factors influencing LOS were operative time, age, BMI, ASA class, levels operated on, etiology, nutritional support, pulmonary and neurologic comorbidities. The gradient boosting model performed best with a test accuracy of 0.723, AUC of 0.630, and a Brier score of 0.189, leading to a patient-specific risk calculator for prolonged LOS., Conclusions: Machine learning algorithms accurately predict extended LOS across a national patient cohort and characterize key preoperative drivers of increased LOS after PSIF in pediatric patients with EOS., (© 2024. The Author(s), under exclusive licence to Scoliosis Research Society.)

Background: This analysis aims to evaluate the methodological quality of Evicore's spinal imaging guidelines for lower extremity pain with neurological features with or without lower back pain by leveraging the AGREE II tool. The AGREE II tool provides a framework to assess guideline development. It is well validated and has been used to evaluate many other guidelines previously., Methods: Five appraisers used the AGREE II appraisal tool to conduct a comprehensive review of Evicore's spinal imaging guidelines for lower extremity pain with neurological features. Appraisers provided an overall assessment of the guidelines as well as specific scores pertaining to domains including scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence., Results: Appraisers assigned numerical grades of 2, 2, 2, 3 and 4 (out of 7 total points, with 7 being the highest) for overall quality of the guidelines. Three appraisers recommended use of the guideline with modifications and two appraisers did not recommend the guideline. The AGREE II ratings had good reliability across the different raters [intraclass correlation coefficient (ICC) =0.881, 95% confidence interval (CI): 0.77, 0.94]., Conclusions: Evicore's guidelines would greatly benefit from increased identification and diversification of guideline development parties and stakeholders, increased rigor of development including a more robust discussion of the body of evidence and its strengths and limitations, and incorporation of more explicit suggestions for implementation of guideline recommendations by healthcare providers., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jss.amegroups.com/article/view/10.21037/jss-22-57/coif). The authors have no conflicts of interest to declare., (2023 Journal of Spine Surgery. All rights reserved.)

With recent advances and anticipated proliferation of lipid nanoparticle (LNP)-delivered vaccines and therapeutics, there is a need for the availability of internationally recognized reference materials of LNP systems. Accordingly, we developed six LNP and liposome (anionic, neutral, and cationic each) candidate reference material formulations and thoroughly characterized by dynamic light scattering their particle hydrodynamic size (Z-avr) and polydispersity. We also evaluated the particle size homogeneity and long-term -70 °C and 4 °C storage stability using multiple large sets of randomly selected vials for each formulation. The formulations stored at -70 °C remained stable and homogeneous for a minimum of 9 months. The Z-avr relative combined uncertainty and the long-term variability were both <1.3% for liposome formulations and anionic LNPs, (3.9% and 1.7%) for neutral LNPs, and (6.7% and 4.4%) for cationic LNPs. An inadvertent few-hour-long storage temperature increase to -35 °C due to a freezer malfunction resulted in a small change of the size and size distribution of anionic liposomes and LNPs but, unexpectedly, a larger size increase of the neutral and cationic liposomes (≤5%) and LNPs (≤25%). The mean Z-avr values of the LNPs stored at 4 °C appeared to slowly increase with t 1/3 , where t is the storage time, and the Z-avr between-vial heterogeneity and mean polydispersity index values appeared to decrease; no change was observed for liposomes. The size and size distribution evolution of LNPs stored at 4 °C was attributed to an incomplete equilibration of the formulations following the addition of sucrose prior to the initial freezing. Such a process of size increase and size distribution narrowing has not been previously discussed nor observed in the context of LNPs.

Current chemoradiation therapy suffers from normal tissue toxicity. Thus, we are proposing incorporating gold nanoparticles (GNPs) and docetaxel (DTX), as they have shown very promising synergetic radiosensitization effects. Here, we explored the effect of a DTX prodrug encapsulated in lipid nanoparticles (LNP DTX-P ) on GNP uptake in pancreatic cancer models in vitro and in vivo. For the in vitro experiment, a pancreatic cancer cell line, MIA PaCa-2, was cultured and dosed with 1 nM GNPs and 45 nM free DTX or an equivalent dose of LNP DTX-P . For the in vivo experiment, MIA PaCa-2 cells were implanted subcutaneously in NRG mice, and the mice were dosed with 2 mg/kg of GNPs and 6 mg/kg of DTX or an equivalent dose of LNP DTX-P . The results show that LNP DTX-P -treated tumour samples had double the amount GNPs compared to control samples, both in vitro and in vivo. The results are very promising, as LNP DTX-P have superior targeting of tumour tissues compared to free DTX due to their nanosize and their ability to be functionalized. Because of their minimal toxicity to normal tissues, both GNPs and LNP DTX-P could be ideal radiosensitization candidates in radiotherapy and would produce very promising synergistic therapeutic outcomes.

Lipid based nanocarriers are one of the most effective drug delivery systems that is evident from the recent COVID-19 mRNA vaccines. The main objective of this study was to evaluate toxicity of six lipid based formulations with three surface charges-anionic, neutral or cationic, to establish certified reference materials (CRMs) for liposomes and siRNA loaded lipid nanoparticles (LNP-siRNA). Cytotoxicity was assessed by a proliferation assay in adherent and non-adherent cell lines. High concentration of three LNP-siRNAs did not affect viability of suspension cells and LNP-siRNAs were non-toxic to adherent cells at conventionally used concentration. Systematic evaluation using multiple vials and repeated test runs of three liposomes and three LNP-siRNA formulations showed no toxicity in HL60 and A549 cells up to 128 and 16 µg/mL, respectively. Extended treatment and low concentration of LNPs did not affect the viability of suspension cells and adherent cells at 96 h. Interestingly, 80% of A549 and HL60 cells in 3D conditions were viable when treated with cationic LNP-siRNA for 48 h. Taken together, anionic, cationic and neutral lipid formulations were non-toxic to cells and may be explored further in order to develop them as drug carriers., (© 2022. Crown.)

Objective: To compare the perioperative results and intermediate-term functional outcomes of single port and multiport robotic-assisted laparoscopic prostatectomy by using a propensity-score analysis., Materials and Methods: We evaluated all patients who underwent robotic prostatectomy by 3 urologic surgeons at our institution between January 2019 and October 2020. Demographic, intraoperative, and postoperative data were collected and assessed. Patients were matched based on body mass index, Gleason group, and prostate volume using the optimal matching method., Results: Overall, 98 and 165 patients underwent single port and multiport robotic prostatectomy, respectively. Following propensity-score matching, 98 multiport cases were matched 1:1 to single port cases. The median operative time was lower for multiport (111.5 vs 147.0 minutes, P = .0000). Single port had a lower median estimated blood loss (50.0 vs 75.0 mL, P = .0006), pain score on postoperative day 0 (1.0 vs 2.0, P = .0004), opioid use at postoperative day 1 (0.0 [IQR 0.0-5.0] vs 0.0 MME [IQR 0.0-7.5], P = .0058), cumulative opioid use (2.0 vs 7.0 MME, P = .0008), and lymph node yield (4.0 vs 7.0 nodes, P = .0051). Single port had a greater percentage of men regain full erectile function by 6 months (23.8% vs 4.8%, P = .002)., Conclusion: The single port robotic system is a safe option for localized prostate cancer treatment, offering superior pain control and comparable perioperative results and intermediate-term functional outcomes compared to the multiport robotic approach., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Telemedicine usage in orthopedic surgery has seen a dramatic increase as a result of the severe acute respiratory syndrome coronavirus 2 pandemic. The purpose of this study was to examine patient perceptions with telemedicine at a large orthopedic practice. Materials and Methods: An anonymous online survey was distributed to all patients who received a telemedicine health visit at our institution for musculoskeletal complaints from March 17 to June 1, 2020. Responses were scored on a 5-point Likert scale (strongly disagree, disagree, neutral, agree, and strongly agree, 1-5) and analyzed by average score and percent reaching top box. Results: A majority of patients (76.5%) were satisfied with their visit, and only 19.2% did not want telemedicine as a future option. Patients who presented for follow-up visits (4.11 vs. 3.94, p  = 0.0053; 48% vs. 41%, p  = 0.02) and utilized video (4.21 vs. 3.88, p < 0.001; 51% vs. 39%, p < 0.001) were more satisfied. Average satisfaction between older (>65 years) and younger patients was similar (4.06 vs. 4.06, p  = 0.97), however, younger patients were more likely to reach top box (42% vs. 51%, p < 0.001). Confidence that the physician came to the correct diagnosis ( r  = 0.78, p < 0.001) and receiving the same information and care as an in-office visit ( r  = 0.60, p < 0.001) demonstrated the strongest correlation with satisfaction and desire for future telemedicine visits, respectively. Interestingly, 31.1% of patients would have sought treatment elsewhere had telemedicine not been an option. Conclusions: Overall, satisfaction rates are high for orthopedic patients undergoing telemedicine visits. Patients are more confident in telemedicine when presenting for a follow-up visit and with the use of video.

Introduction and Objective: Scant literature is available on surgical outcomes of radical cystectomies on the new single-port (SP) system. This study compares short-term outcomes in patients undergoing radical cystectomy with those undergoing intracorporeal urinary diversion (ICUD) on the multiport (MP) vs SP platform. Methods: This institutional review board approved study used a prospective cystectomy database and nonparametric testing including chi-squared, Mann-Whitney U, and Fisher exact tests to analyze all variables stratified by surgical approach. Results: Thirty-four patients underwent radical cystectomy with ICUD from September 1, 2019, to February 8, 2021. Twenty patients were in the MP cohort, whereas 14 were in the SP group. Table 1 presents the demographics of both groups and shows no statistically significant differences. Intra- and postoperative as well as pathology data are given in Table 2. Patients in the SP group had less narcotic use (MP: 25 morphine milligram equivalent [MME] vs SP: 11.5 MME, p  = 0.047) and shorter return of bowel function (MP: 3 days vs SP: 2 days, p  = 0.032). Operative times were similar between both groups despite having fewer patients undergoing ileal conduit (MP: 85% vs SP: 50%, p  = 0.027) in the SP group. In Table 3, we list the early short-term postoperative follow-up data for each group that showed no significant differences between the two groups with an average follow-up of 4.9 months for MP and 4.4 months for SP. Conclusions: Our initial experience with SP robotic cystectomy and ICUD appears to be safe and an effective alternative to MP cystectomies. A learning curve was involved but the overall transition from MP to SP was smooth. Operative times were similar despite fewer patients undergoing ileal diversion, shorter return of bowel function, and less narcotic use in the SP group. Further studies including longer follow-ups with multi-institutional data are underway.

Successfully employing small interfering RNA (siRNA) therapeutics requires the use of nanotechnology for efficient intracellular delivery. Lipid nanoparticles (LNPs) have enabled the approval of various nucleic acid therapeutics. A major advantage of LNPs is the interchangeability of its building blocks and RNA payload, which allow it to be a highly modular system. In addition, drug derivatization approaches can be used to synthesize lipophilic small molecule prodrugs that stably incorporate in LNPs. This provides ample opportunities to develop combination therapies by co-encapsulating multiple therapeutic agents in a single formulation. Here, it is described how the modular LNP platform is applied for combined gene silencing and chemotherapy to induce additive anticancer effects. It is shown that various lipophilic taxane prodrug derivatives and siRNA against the androgen receptor, a prostate cancer driver, can be efficiently and stably co-encapsulated in LNPs without compromising physicochemical properties or gene-silencing ability. Moreover, it is demonstrated that the combination therapy induces additive therapeutic effects in vitro. Using a double-radiolabeling approach, the pharmacokinetic properties and biodistribution of LNPs and prodrugs following systemic administration in tumor-bearing mice are quantitatively determined. These results indicate that co-encapsulating siRNA and lipophilic prodrugs into LNPs is an attractive and straightforward plug-and-play approach for combination therapy development., (© 2021 The Authors. Small published by Wiley-VCH GmbH.)

In 2020, the coronavirus disease 2019 (COVID-19) pandemic limited musculoskeletal care to urgent or "nonelective" office visits and procedures. No guidelines exist to inform patients or physicians what meets these criteria. The purpose of this multi-institutional study was to describe the differences in perceptions of urgency for musculoskeletal complaints between patients and providers during the COVID-19 pandemic. An anonymous survey was distributed to patients who visited the authors' orthopedic clinics in January and February 2020 and practicing orthopedic surgeons. The surveys were administered in May 2020 after COVID-19 was officially labeled a pandemic and included questions regarding demographic information and perceptions of orthopedic urgency. A total of 1491 patients and 128 physicians completed the surveys. A significantly higher percentage of physicians considered the following diagnoses an appropriate indication for an urgent visit compared with patients: fracture ( P <.001), acute dislocation ( P <.001), infection ( P <.001), neurologic compromise ( P <.001), tumor ( P <.001), acute tendon injury ( P <.001), weakness ( P <.001), inability to bear weight ( P <.001), post-surgical problem ( P <.001), and painful joint effusion ( P <.001). There were no significant differences in the perception of urgency for the following conditions: bursitis/tendonitis ( P =1.00), joint/extremity deformity without pain ( P =.113), and loss of range of motion of a joint ( P =.467). Younger patients and those with higher levels of education were significantly more likely to consider their conditions urgent. Patients may require additional education to prevent delay in treatment of urgent conditions-especially time-sensitive conditions such as neurologic compromise, tumors, and infections-when access to physicians is limited. [ Orthopedics . 2021;44(4):e534-e538.].

Previous work suggested that lipid nanoparticle (LNP) formulations, encapsulating nucleic acids, display electron-dense morphology when examined by cryogenic-transmission electron microscopy (cryo-TEM). Critically, the employed cryo-TEM method cannot differentiate between loaded and empty LNP formulations. Clinically relevant formulations contain high lipid-to-nucleic acid ratios (10-25 (w/w)), and for systems that contain mRNA or DNA, it is anticipated that a substantial fraction of the LNP population does not contain a payload. Here, we present a method based on the global analysis of multi-wavelength sedimentation velocity analytical ultracentrifugation, using density matching with heavy water, that not only measures the standard sedimentation and diffusion coefficient distributions of LNP mixtures, but also reports the corresponding partial specific volume distributions and optically separates signal contributions from nucleic acid cargo and lipid shell. This makes it possible to reliably predict molar mass and anisotropy distributions, in particular, for systems that are heterogeneous in partial specific volume and have low to intermediate densities. Our method makes it possible to unambiguously measure the density of nanoparticles and is motivated by the need to characterize the extent to which lipid nanoparticles are loaded with nucleic acid cargoes. Since the densities of nucleic acids and lipids substantially differ, the measured density is directly proportional to the loading of nanoparticles. Hence, different loading levels will produce particles with variable density and partial specific volume. An UltraScan software module was developed to implement this approach for routine analysis.

DNA damage repair genes are modifiers of disease onset in Huntington's disease (HD), but how this process intersects with associated disease pathways remains unclear. Here we evaluated the mechanistic contributions of protein inhibitor of activated STAT-1 (PIAS1) in HD mice and HD patient-derived induced pluripotent stem cells (iPSCs) and find a link between PIAS1 and DNA damage repair pathways. We show that PIAS1 is a component of the transcription-coupled repair complex, that includes the DNA damage end processing enzyme polynucleotide kinase-phosphatase (PNKP), and that PIAS1 is a SUMO E3 ligase for PNKP. Pias1 knockdown (KD) in HD mice had a normalizing effect on HD transcriptional dysregulation associated with synaptic function and disease-associated transcriptional coexpression modules enriched for DNA damage repair mechanisms as did reduction of PIAS1 in HD iPSC-derived neurons. KD also restored mutant HTT-perturbed enzymatic activity of PNKP and modulated genomic integrity of several transcriptionally normalized genes. The findings here now link SUMO modifying machinery to DNA damage repair responses and transcriptional modulation in neurodegenerative disease., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Lipid nanoparticle (LNP) formulations of nucleic acid are leading vaccine candidates for COVID-19, and enabled the first approved RNAi therapeutic, Onpattro. LNPs are composed of ionizable cationic lipids, phosphatidylcholine, cholesterol, and polyethylene glycol (PEG)-lipids, and are produced using rapid-mixing techniques. These procedures involve dissolution of the lipid components in an organic phase and the nucleic acid in an acidic aqueous buffer (pH 4). These solutions are then combined using a continuous mixing device such as a T-mixer or microfluidic device. In this mixing step, particle formation and nucleic acid entrapment occur. Previous work from our group has shown that, in the absence of nucleic acid, the particles formed at pH 4 are vesicular in structure, a portion of these particles are converted to electron-dense structures in the presence of nucleic acid, and the proportion of electron-dense structures increases with nucleic acid content. What remained unclear from previous work was the mechanism by which vesicles form electron-dense structures. In this study, we use cryogenic transmission electron microscopy and dynamic light scattering to show that efficient siRNA entrapment occurs in the absence of ethanol (contrary to the established paradigm), and suggest that nucleic acid entrapment occurs through inversion of preformed vesicles. We also leverage this phenomenon to show that specialized mixers are not required for siRNA entrapment, and that preformed particles at pH 4 can be used for in vitro transfection.

The success of Onpattro™ (patisiran) clearly demonstrates the utility of lipid nanoparticle (LNP) systems for enabling gene therapies. These systems are composed of ionizable cationic lipids, phospholipid, cholesterol, and polyethylene glycol (PEG)-lipids, and are produced through rapid-mixing of an ethanolic-lipid solution with an acidic aqueous solution followed by dialysis into neutralizing buffer. A detailed understanding of the mechanism of LNP formation is crucial to improving LNP design. Here we use cryogenic transmission electron microscopy and fluorescence techniques to further demonstrate that LNP are formed through the fusion of precursor, pH-sensitive liposomes into large electron-dense core structures as the pH is neutralized. Next, we show that the fusion process is limited by the accumulation of PEG-lipid on the emerging particle. Finally, we show that the fusion-dependent mechanism of formation also applies to LNP containing macromolecular payloads including mRNA, DNA vectors, and gold nanoparticles.

Lipid nanoparticles (LNPs) are playing a leading role in enabling clinical applications of gene therapies based on DNA or RNA polymers. One factor impeding clinical acceptance of LNP therapeutics is that LNP formulations of nucleic acid polymers can be immunostimulatory, necessitating co-administration of potent corticosteroid immunosuppressive agents. Here, we describe the development of hydrophobic prodrugs of a potent corticosteroid, dexamethasone, that can be readily incorporated into LNP systems. We show that the presence of the dexamethasone prodrug LD003 effectively suppresses production of cytokines such as KC-GRO, TNFα, IL-1β and IL-6 following intravenous administration of LNP loaded with immune stimulatory oligodeoxynucleotides containing cytosine-guanine dinucleotide motifs. Remarkably, LD003 dose levels corresponding to 0.5 mg/kg dexamethasone achieve a greater immunosuppressive effect than doses of 20 mg/kg of free dexamethasone. Similar immunosuppressive effects are observed for subcutaneously administered LNP-siRNA. Further, the incorporation of low levels of LD003 in LNP containing unmodified mRNA or plasmid DNA significantly reduced pro-inflammatory cytokine levels following intravenous administration. Our results suggest that incorporation of hydrophobic prodrugs such as LD003 into LNP systems could provide a convenient method for avoiding the immunostimulatory consequences of systemic administration of genetic drug formulations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A straightforward "bottom-up" synthesis is described for efficient entrapment of inorganic hydrophobic nanoparticles (HNPs) consisting of iron oxide, gold, or quantum dots within the hydrophobic core of lipid nanoparticles (LNPs). These LNPs consist of hydrophobic "core" lipids such as triolein surrounded by a monolayer of amphipathic "surface" lipids, such as phosphatidylcholine and polyethylene-glycol-lipid. It is shown that rapid, controlled mixing of HNPs, core lipids and surface lipids in an organic solvent with an aqueous phase resulted in stable, monodisperse LNPs containing HNPs (LNP-HNP). This method allows 40-fold more hydrophobic iron oxide nanoparticles (IONPs) to be entrapped within an LNP than previous methods and can be readily extended to encapsulate other HNPs. The LNP-HNP diameter can be modulated over the range of 35-150 nm by varying the flow rate during particle synthesis or by varying the core-to-surface lipid ratio. LNP-IONPs can be generated using a variety of "core" lipids, including other triglycerides as well as cholesteryl-palmitate and tocopherol. Finally, it is shown that LNP-IONPs are accumulated in the liver, resulting in enhanced contrast for in vivo MRI. It is concluded that the bottom-up approach for encapsulating HNPs within LNPs has advantages of homogeneity, reproducibility and stability required for biomedical applications.

The therapeutic applications of lipid nanoparticle (LNP) formulations of small interfering RNA (siRNA), are hampered by inefficient delivery of encapsulated siRNA to the cytoplasm following endocytosis. Recent work has shown that up to 70% of endocytosed LNP-siRNA particles are recycled to the extracellular medium and thus cannot contribute to gene silencing. Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal membrane protein required for efficient extracellular recycling of endosomal contents. Here we assess the influence of NP3.47, a putative small molecule inhibitor of NPC1, on the gene silencing potency of LNP-siRNA systems in vitro. Intracellular uptake and colocalization studies revealed that the presence of NP3.47 caused threefold or higher increases in accumulation of LNP-siRNA in late endosomes/lysosomes as compared with controls in a variety of cell lines. The gene silencing potency of LNP siRNA was enhanced up to fourfold in the presence of NP3.47. Mechanisms of action studies are consistent with the proposal that NP3.47 acts to inhibit NPC1. Our findings suggest that the pharmacological inhibition of NPC1 is an attractive strategy to enhance the therapeutic efficacy of LNP-siRNA by trapping LNP-siRNA in late endosomes, thereby increasing opportunities for endosomal escape.

Oxidative amidation chemistry provides a unified route to aromatic Erythrina alkaloids through a sequence that illustrates new principles and improved conditions to effect a crucial eliminative Curtius-Schmidt rearrangement.

Gene silencing activity of lipid nanoparticle (LNP) formulations of siRNA requires LNP surface factors promoting cellular uptake. This study aimed to identify small molecules that enhance cellular uptake of LNP siRNA systems, then use them as LNP-associated ligands to improve gene silencing potency. Screening the Canadian Chemical Biology Network molecules for effects on LNP uptake into HeLa cells found that cardiac glycosides like ouabain and strophanthidin caused the highest uptake. Cardiac glycosides stimulate endocytosis on binding to plasma membrane Na(+)/K(+) ATPase found in all mammalian cells, offering the potential to stimulate LNP uptake into various cell types. A PEG-lipid containing strophanthidin at the end of PEG (STR-PEG-lipid) was synthesized and incorporated into LNP. Compared to non-liganded systems, STR-PEG-lipid enhanced LNP uptake in various cell types. Furthermore, this enhanced uptake improved marker gene silencing in vitro. Addition of STR-PEG-lipid to LNP siRNA may have general utility for enhancing gene silencing potency., From the Clinical Editor: In this study, the authors identified small molecules that enhance cellular uptake of lipid nanoparticle siRNA systems, then used them as LNP-associated ligands to improve gene silencing potency., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Lithiation of BF 3-complexed dimethylaminoferrocene occurs exclusively ortho to the dimethylamino group in the cyclopentadienyl ring providing structurally diverse products in 76-94% yield after electrophile quench. This method represents the first direct C2-lithiation of a monosubstituted aminoferrocene, offering rapid and complementary access to this class of compounds over procedures that utilize carbon- and sulfur-based directing groups and may serve as a prelude to an asymmetric process.

The inability of bis-N-Boc-protected octahydrophenanthroline to undergo asymmetric lithiation with (-)-sparteine is circumvented by use of a urea functionality as the directing group. Asymmetric lithiation followed by electrophile quench gives products substituted alpha to nitrogen in better yield (17-30%) but slightly lower enantiomeric ratio (er 84:16) than analogous lithiation of N-Boc-piperidine (er 87:13). Computational studies at the MP2/6-316(d)//B3LYP/6-316(d) level indicate that the prochiral equatorial S-hydrogen is removed preferentially over the pro-R hydrogen, with a difference in transition state activation energies of 1.26 kcal/mol, corresponding to a predicted er of 89:11. The predicted stereochemistry of the reaction was confirmed by single-crystal X-ray analysis of an aryl dibromide prepared from the enantiomerically enriched alpha-methyl-substituted product.