Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway.

The complement alternative pathway (AP) is implicated in numerous diseases affecting many organs, ranging from the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH), to the common blinding disease age-related macular degeneration (AMD). Critically, the AP amplifies any activating trigger driving a downstream inflammatory response; thus, components of the pathway have become targets for drugs of varying modality. Recent validation from clinical trials using drug modalities such as inhibitory antibodies has paved the path for gene targeting of the AP or downstream effectors. Gene targeting in the complement field currently focuses on supplementation or suppression of complement regulators in AMD and PNH, largely because the eye and liver are highly amenable to drug delivery through local (eye) or systemic (liver) routes. Targeting the liver could facilitate treatment of numerous diseases as this organ generates most of the systemic complement pool. This review explains key concepts of RNA and DNA targeting and discusses assets in clinical development for the treatment of diseases driven by the alternative pathway, including the RNA-targeting therapeutics ALN-CC5, ARO-C3, and IONIS-FB-LRX, and the gene therapies GT005 and HMR59. These therapies are but the spearhead of potential drug candidates that might revolutionize the field in coming years.

AAV2 vector optimization for retinal ganglion cell-targeted delivery of therapeutic genes.

Recombinant adeno-associated virus (AAV)-2 has significant potential as a delivery vehicle of therapeutic genes to retinal ganglion cells (RGCs), which are key interventional targets in optic neuropathies. Here we show that when injected intravitreally, AAV2 engineered with a reporter gene driven by cytomegalovirus (CMV) enhancer and chicken ß-actin (CBA) promoters, displays ubiquitous and high RGC expression, similar to its synthetic derivative AAV8BP2. A novel AAV2 vector combining the promoter of the human RGC-selective γ-synuclein (hSNCG) gene and woodchuck hepatitis post-transcriptional regulatory element (WPRE) inserted upstream and downstream of a reporter gene, respectively, induces widespread transduction and strong transgene expression in RGCs. High transduction efficiency and selectivity to RGCs is further achieved by incorporating in the vector backbone a leading CMV enhancer and an SV40 intron at the 5' and 3' ends, respectively, of the reporter gene. As a delivery vehicle of hSIRT1, a 2.2-kb therapeutic gene with anti-apoptotic, anti-inflammatory and anti-oxidative stress properties, this recombinant vector displayed improved transduction efficiency, a strong, widespread and selective RGC expression of hSIRT1, and increased RGC survival following optic nerve crush. Thus, AAV2 vector carrying hSNCG promoter with additional regulatory sequences may offer strong potential for enhanced effects of candidate gene therapies targeting RGCs.

Phase I Safety and Feasibility Pilot of Hepatic Artery Infusion Chemotherapy in a Rural Catchment Area Using The Codman Vascular Catheter with The Medtronic SynchroMed II Pump for Intrahepatic Cancers.

BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.

Defining the patient acceptable symptom state using PROMIS following reconstruction of the progressive collapsing foot deformity.

BACKGROUND: The patient acceptable symptom state (PASS) represents the threshold beyond which patients are satisfied with their outcome. This study aimed to define PASS thresholds for progressive collapsing foot deformity (PCFD) reconstruction using Patient-Reported Outcomes Measurement Information System (PROMIS) scores and anchor question responses. METHODS: This retrospective study consisted of 109 patients who underwent flexible PCFD reconstruction, had preoperative and 2-year postoperative PROMIS scores, and 2-year postoperative anchor question responses. ROC curve analyses were performed to quantify PASS thresholds. RESULTS: PASS thresholds for the PROMIS Physical Function (PF) and Pain Interference (PI) domains were found to be lower and higher, respectively, than population norms. Furthermore, patients with higher preoperative PROMIS PF scores or lower preoperative PROMIS PI scores had a significantly higher likelihood of achieving the PASS thresholds. CONCLUSION: In addition to guiding future outcomes research, these results may help surgeons optimize treatment for PCFD and better manage patient expectations. LEVEL OF EVIDENCE: III, retrospective cohort study.

Incidence and predictors of valgus tibiotalar tilt after progressive collapsing foot deformity reconstruction using subtalar fusion with concomitant procedures.

PURPOSE: Development of valgus tibiotalar tilt is a significant complication after subtalar fusion for progressive collapsing foot deformity (PCFD) correction. However, its incidence and etiologic factors have not been extensively studied. The purpose of this study was to define the incidence of valgus tibiotalar tilt after subtalar fusion for PCFD reconstruction, and to determine predictors of this complication. METHODS: This study included 59 patients who underwent PCFD reconstruction with subtalar fusion. Patients with tibiotalar tilt prior to surgery were excluded. On standard weightbearing radiographs, the talonavicular coverage angle, talo-1st metatarsal angle, calcaneal pitch, hindfoot moment arm (HMA), and medial distal tibial angle were measured. Weightbearing computed tomography (WBCT) was used to determine the presence of lateral bony impingement. A radiologist evaluated the superficial and deep deltoid ligaments using magnetic resonance imaging (MRI). Univariate regression analysis was used to identify the factors associated with development of postoperative valgus tibiotalar tilt, defined as tilt > 2 degrees. RESULTS: Seventeen patients (28.8%) developed postoperative valgus tibiotalar tilt at a mean of 7.7 (range 2-31) months. Eight (47.1%) of these patients developed valgus tibiotalar tilt within 3 months. Univariate logistic regression demonstrated association between preoperative HMA and postoperative valgus tibiotalar tilt (odds ratio 1.06, P = 0.026), with a 6% increase in risk per millimeter of increased HMA. Deltoid ligament status and concomitant procedures on other joints did not correlate with postoperative valgus tilt. CONCLUSION: Our findings indicate that surgeons should be cognizant of patients with a greater degree of preoperative hindfoot valgus and their propensity to develop a valgus ankle deformity. Additionally, our relatively high incidence of valgus tibiotalar tilt suggests that weightbearing ankle radiographs should be included in the initial and subsequent follow-up of PCFD patients with hindfoot valgus treated with subtalar fusion.

Finite Element Modeling of Planus and Rectus Foot Types for the Study of First Metatarsophalangeal and First Metatarsocuneiform Joint Contact Mechanics.

The foot is a highly complex biomechanical system for which finite element (FE) modeling has been used to evaluate its loading environment. However, there is limited knowledge of first metatarsophalangeal (MTP) and first metatarsocuneiform (MTC) joint contact mechanics. Our goal was to develop a framework for FE modeling of the medial forefoot which could accurately predict experimental measurements of first MTP and first MTC joint loading. Simulations of planus and rectus foot types were conducted for midstance of gait. A custom-built force-controlled cadaveric test-rig was used to derive intracapsular pressure sensor measurements of contact pressure, force, and area during quasi-static loading. The FE model was driven under the same boundary and loading conditions as the cadaver. Mesh sensitivity analyses and best-fit calibrations of moduli for first MTP and first MTC joint cartilage were performed. Consistent with previous experimental research, a lower compressive modulus was best-fit to the first MTP compared to first MTC joint at 10 MPa and 20 MPa, respectively. Mean errors in contact pressures, forces, and areas were 24%, 4%, and 40% at the first MTP joint and 23%, 12%, and 19% at the first MTC joint, respectively. The present developmental framework may provide a basis for future modeling of first MTP and first MTC joint contact mechanics. This study acts as a precursor to validation of realistic physiological loading across gait to investigate joint loading, foot type biomechanics, and surgical interventions of the medial forefoot.

Chronic Achilles Tendon Ruptures: From Bracing Treatment to Complex Reconstruction.

The optimal management of chronic Achilles tendon injuries continues to be debated. The tension-length relationship and intrinsic viscoelasticity of the native tendon that allows efficient propulsion during ambulation are difficult to restore once the tendon has been injured. Missed or misdiagnosed injuries or failure of surgical or nonsurgical management of acute Achilles tendon ruptures can lead to the tendon healing in an elongated position or lack of healing altogether. This condition results in persistent weakness, pain, and functional debilitation for the patient. Understanding the tendon and muscle properties will inform the choice of treatment. Nonsurgical treatment options are primarily bracing treatment and physical therapy. Surgical treatment options involve direct repair, reconstruction with local tissue, allograft or autograft, and tendon transfer. Various options and techniques for reconstruction are described to assist in optimizing management of this challenging clinical problem.

The influence of concomitant hammertoe correction on postoperative outcomes in patients undergoing hallux valgus correction.

BACKGROUND: Patients with hallux valgus often develop secondary hammertoe deformities of the lesser toes. Operative management of bunions with hammertoe can be more extensive; however, it is unclear whether this affects patient-reported outcomes. The aim of this study was to compare postoperative patient-reported outcome measures and radiographic outcomes between patients who underwent isolated bunion correction and patients who underwent simultaneous bunion and hammertoe correction. METHODS: Preoperative, postoperative, and change in Patient-Reported Outcomes Measurement Information System (PROMIS) scores were compared between patients who underwent isolated hallux valgus correction and those who underwent concomitant hammertoe correction. Radiographic measures including hallux valgus angle (HVA), intermetatarsal angle (IMA), distal metatarsal-articular angle (DMAA), and Meary's angle were also compared. Targeted minimum-loss estimation (TMLE) was used for statistical analysis to control for confounders. RESULTS: A total of 221 feet (134 isolated bunion correction, 87 concomitant hammertoe correction) with a minimum of 12 months follow-up were included in this study. Both cohorts demonstrated significant improvements in the physical function, pain interference, pain intensity, and global physical health PROMIS domains (all p < 0.001). However, patients in the concomitant hammertoe cohort had significantly less improvements in pain interference and pain intensity (p < 0.01, p < 0.05 respectively). The concomitant hammertoe cohort also had significantly higher postoperative pain interference scores than the isolated bunion cohort (p < 0.01). Radiographic outcomes did not differ between the two groups. CONCLUSION: While both isolated bunion correction and concomitant hammertoe correction yielded clinically significant improvements in patient reported outcomes and normalized radiographic parameters, patients undergoing simultaneous bunion and hammertoe correction experienced substantially less improvement in postoperative pain-related outcomes than those who underwent isolated bunion correction.

Mid-term functional outcomes following reoperation after total ankle arthroplasty: A retrospective cohort study.

BACKGROUND: Despite a significant reported rate of non-revision reoperation after total ankle arthroplasty (TAA), it is uncertain if these subsequent procedures have an impact on the longer term outcomes. This study aimed to compare minimum five-year functional outcomes of patients who had undergone reoperation after TAA to those who did not require reoperation. METHODS: Seventy-six ankles (74 patients) who underwent TAA with the Salto Talaris fixed bearing system between 2007 and 2014 were allocated into two groups based on presence (n = 16) or absence of reoperation (n = 60). Reoperations included all secondary procedures after index TAA, excluding revision surgeries requiring removal or exchange of the original prosthesis. The foot and ankle outcome score (FAOS) at preoperative and minimum five-year follow-up was compared between the groups. Additionally, improvements in FAOS subscales were compared. Preoperative deformity, postoperative implant alignment, number of periprosthetic cysts, and subsidence between groups were compared using standard weightbearing radiographs. RESULTS: The most common cause of reoperation was gutter impingement (n = 11), followed by stress fracture of the medial malleolus (n = 2), tarsal tunnel syndrome (n = 1), periprosthetic cyst (n = 1), and infection (n = 1). In comparison to the non-reoperation group, all FAOS subscales except for the Sports and Recreational Activities subscale were significantly lower in the reoperation group at final follow-up. The reoperation group exhibited significantly less improvement in the Pain, Symptoms, and Quality of Life subscales at final follow-up (p < 0.05). There were no statistical differences in the radiographic parameters between both groups. CONCLUSIONS: Patients who underwent reoperation after TAA demonstrated inferior functional outcomes at mid-term follow-up. An emphasis should be placed on preventing possible causes of reoperations to achieve favorable patient outcomes. Additionally, if a reoperation is deemed necessary, a thorough evaluation and surgical correction of underlying causes should be achieved.

Pronation on weightbearing radiographs does not correlate with pronation from weightbearing CT scans.

INTRODUCTION: In hallux valgus (HV), first metatarsal pronation is increasingly recognized as an important aspect of the deformity. The purpose of this study was to compare pronation in HV patients determined from the shape of the lateral head of the first metatarsal on AP weightbearing radiographs with pronation calculated from weightbearing CT (WBCT) scans. METHODS: Patients were included in this study if they had preoperative and 5-month postoperative WBCT scans and corresponding weightbearing AP radiographs of the affected foot. Pronation of the first metatarsal on WBCT scans was measured using a 3D CAD model and the alpha angle and categorized into four groups on radiographs. Association between pronation groups on radiographs and WBCT scans was determined using Spearman correlation coefficients (rs) and by comparing mean WBCT pronation of the first metatarsal between plain radiograph pronation groups. RESULTS: Agreement between the two observers' pronation on radiographs was good (k = 0.634) and moderate (k = 0.501), respectively. There was no correlation between radiographic pronation and the 3D CAD model (rs < 0.15). Preoperatively, there was weak correlation between the alpha angle and the radiographic pronation groups (rs = 0.371, P = 0.048) although this relationship did not hold postoperatively (rs = 0.330, P = 0.081). There was no difference in mean pronation calculated on WBCT scans between the plain radiographic groups. CONCLUSION: Pronation of the first metatarsal measured on weightbearing AP radiographs had moderate interobserver agreement and was only weakly associated with pronation measured from WBCT scans. These results suggest that first metatarsal pronation measured on weightbearing radiographs is not a substitute for pronation measured on WBCT scans. LEVEL OF EVIDENCE: III, retrospective cohort study.

The use of three-dimensional biometric Foot and Ankle Offset to predict additional realignment procedures in total ankle replacement.

BACKGROUND: Decision to perform associated corrective alignment procedures in patients undergoing total ankle replacement (TAR) is commonly made intraoperatively. The Foot and Ankle Offset (FAO) can evaluate multiplanar deformity and be an effective instrument in surgical planning. This study objective was to assess the ability of this tool to predict the need for additional realignment procedures at the time of TAR. METHODS: In this retrospective study, we enrolled 21 patients who underwent TAR and had preoperative WBCT studies. Two independent and blinded observers calculated the preoperative FAO using dedicated software. FAO measurements were compared between the different alignment groups (physiological alignment, valgus and varus). A multivariate regression analysis was used to assess the correlation between performed realignment procedures and FAO values. RESULTS: Mean preoperative FAO was 4.4% (95%CI = 1.4-7.5). The number of osseous realignment procedures needed was found to correlate positively and significantly with FAO (p = .001). The number of osseus procedures needed was significantly higher in patients with valgus malalignment (p = .009). Patients with valgus malalignment needing a medial column procedure had a relative risk of 6.3 when compared to varus malalignment patients (p = .02). CONCLUSION: The number of additional bony realignment procedures performed at the time of TAR significantly correlated with preoperative FAO and that the number of osseus procedures needed was significantly higher in patients with valgus malalignment. Such biometric tools may enhance the preoperative assessment and surgical planning for patients undergoing TAR, with the potential to optimize surgical outcomes.

Combined weightbearing CT and MRI assessment of flexible progressive collapsing foot deformity.

BACKGROUND: The objective of this study was to evaluate the correlation between Weightbearing CT (WBCT) markers of pronounced peritalar subluxation (PTS) and MRI findings of soft tissue insufficiency in patients with flexible Progressive Collapsing Foot Deformity (PCFD). We hypothesized that significant correlation would be found. METHODS: Retrospective comparative study with 54 flexible PCFD patients. WBCT and MRI variables deformity severity were evaluated, including markers of pronounced PTS, as well as soft tissue degeneration. A multiple regression analysis and partition prediction models were used to evaluate the relationship between bone alignment and soft tissue injury. P-values of less than .05 were considered significant. RESULTS: Degeneration of the posterior tibial tendon was significantly associated with sinus tarsi impingement (p = .04). Spring ligament degeneration correlated to subtalar joint subluxation (p = .04). Talocalcaneal interosseous ligament involvement was the only one to significantly correlate to the presence of subfibular impingement (p = .02). CONCLUSION: Our results demonstrated that WBCT markers of pronounced deformity and PTS were significantly correlated to MRI involvement of the PTT and other important restraints such as the spring and talocalcaneal interosseus ligaments. LEVEL OF EVIDENCE: Level III, Retrospective comparative study.

Weight-bearing radiographs and cone-beam computed tomography examinations in adult acquired flatfoot deformity.

BACKGROUND: Optimal characterization of Adult acquired flatfoot deformity (AAFD) on two-dimensional radiograph can be challenging. Weightbearing Cone Beam CT (CBCT) may improve characterization of the three-dimensional (3D) structural details of such dynamic deformity. We compared and validated AAFD measurements between weightbearing radiograph and weightbearing CBCT images. METHODS: 20 patients (20 feet, right/left: 15/5, male/female: 12/8, mean age: 52.2) with clinical diagnosis of flexible AAFD were prospectively recruited and underwent weightbearing dorsoplantar (DP) and lateral radiograph as well as weightbearing CBCT. Two foot and ankle surgeons performed AAFD measurements at parasagittal and axial planes (lateral and DP radiographs, respectively). Intra- and Inter-observer reliabilities were calculated by Intraclass correlation (ICC) and Cohen's kappa. Mean values of weightbearing radiograph and weightbearing CBCT measurements were also compared. RESULTS: Except for medial-cuneiform-first-metatarsal-angle, adequate intra-observer reliability (range:0.61-0.96) was observed for weightbearing radiographic measurements. Moderate to very good interobserver reliability between weightbearing radiograph and weightbearing CBCT measurements were observed for the following measurements: Naviculocuneiform-angle (ICC:0.47), Medial-cuneiform-first-metatarsal-gapping (ICC:0.58), cuboid-to-floor-distance (ICC:0.68), calcaneal-inclination-angle(ICC:0.7), axial Talonavicular-coverage-angle(ICC:0.56), axial Talus-first-metatarsal-angle(ICC:0.62). Comparing weightbearing radiograph and weightbearing CBCT images, statistically significant differences in the mean values of parasagittal talus-first-metatarsal-angle, medial-cuneiform-first-metatarsal-angle, medial-cuneiform-to-floor-distance and navicular-to-floor-distance was observed (P < 0.05). CONCLUSION: Moderate to very good correlation was observed between certain weightbearing radiograph and weightbearing CBCT measurements, however, significant difference was observed between a number of AAFD measurements, which suggest that 2D radiographic evaluation could potentially underestimate the severity of AAFD, when compared to 3D weightbearing CT assessment.

Customization scenarios for de-identification of clinical notes.

BACKGROUND: Automated machine-learning systems are able to de-identify electronic medical records, including free-text clinical notes. Use of such systems would greatly boost the amount of data available to researchers, yet their deployment has been limited due to uncertainty about their performance when applied to new datasets. OBJECTIVE: We present practical options for clinical note de-identification, assessing performance of machine learning systems ranging from off-the-shelf to fully customized. METHODS: We implement a state-of-the-art machine learning de-identification system, training and testing on pairs of datasets that match the deployment scenarios. We use clinical notes from two i2b2 competition corpora, the Physionet Gold Standard corpus, and parts of the MIMIC-III dataset. RESULTS: Fully customized systems remove 97-99% of personally identifying information. Performance of off-the-shelf systems varies by dataset, with performance mostly above 90%. Providing a small labeled dataset or large unlabeled dataset allows for fine-tuning that improves performance over off-the-shelf systems. CONCLUSION: Health organizations should be aware of the levels of customization available when selecting a de-identification deployment solution, in order to choose the one that best matches their resources and target performance level.

Resonance Raman Characterization of Tetracene Monomer and Nanocrystals: Excited State Lattice Distortions With Implications For Efficient Singlet Fission.

The characterization of specific phonon modes and exciton states that lead to efficient singlet fission (SF) may be instrumental in the design of the next generation of high-efficiency photovoltaic devices. To this end, we analyze the absolute resonance Raman (RR) cross sections for tetracene (Tc) both as a monomer in solution and as a crystalline solid in an aqueous suspension of nanocrystals. For both systems, a time-dependent wavepacket model is developed that is consistent with the absolute RR cross sections, the magnitude of the absorption cross sections, and the vibronic line shapes of the fluorescence. In the monomer, the intramolecular reorganization energy is between 1500 and 1800 cm-1 and the solvent reorganization energy is 70 cm-1. In nanocrystals, the total reorganization is diminished to less than 600 cm-1. The lowest energy exciton has an estimated intramolecular reorganization energy between 300 and 500 cm-1 while intermolecular librational phonons have a reorganization energy of about 130 cm-1. The diminished reorganization energy of the nanocrystal is interpreted in the context of the delocalization of the band-edge exciton onto about ∼7 molecules. When electron and electron-hole correlations are included within many-body perturbation theory, the polarized absorption spectra of crystalline Tc are calculated and found to be in agreement with experiment. The low-lying exciton states and optically active phonons that contribute to the polarized crystal absorption are identified. The likely role of coherent exciton phonon evolution in the SF process is discussed.

Accuracy of patient-specific instrumentation in total ankle arthroplasty: A comparative study.

BACKGROUND: Patient-specific instrumentation (PSI) for TAA is a novel technology with several potential benefits. The primary goal of this study was to compare the use of PSI with the standard referencing guide (SRG) in regards to accuracy of tibial implant positioning. Operative time, fluoroscopy time and accuracy of PSI preoperative reports were also evaluated. METHODS: A retrospective analysis of 99 patients who underwent a primary TAA with the INFINITY prosthesis (Wright Medical, Memphis, TN) was performed. Patients were divided in two groups based on the type of instrumentation used during the TAA (75 in the PSI group vs 24 in the SRG group). There was no significant difference between groups in regards to age at the time of surgery (P=0.122), sex (P=0.138), number of concomitant procedures performed during surgery (P=0.567) and etiology (P=0.841). However, preoperative deformity was significantly smaller in the PSI group (P=0.002). RESULTS: Tibial implant positioning was similar between groups. In the coronal plane, the absolute deviation of the tibial implant from the intended alignment was 1.7±1.4° for the SRG and 1.6±1.2° for PSI (P=0.710). In the sagittal plane, the absolute alignment deviation of the tibial implant was 1.8±1.4° for the SRG and 1.9±1.5° for PSI (P=0.675). Operative time (167 vs 190min, P=0.040) and fluoroscopy time (85 vs 158s, P<0.001) were significantly decreased in the PSI group. The PSI preoperative plan report correctly predicted the implant size in 73% of cases for the tibial component and in 51% of cases for the talar component. CONCLUSIONS: PSI provided similar tibial component alignment as standard instrumentation. Additionally, PSI preoperative plan reports were poor predictors of implant sizing. Therefore, the final decision should always be based on surgeon's experience in order to prevent errors in implant sizing and positioning. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Difference Bands in Time-Resolved Femtosecond Stimulated Raman Spectra of Photoexcited Intermolecular Electron Transfer from Chloronaphthalene to Tetracyanoethylene.

The time-resolved femtosecond stimulated Raman spectra (FSRS) of a charge transfer (CT) excited noncovalent complex tetracyanoethylene:1-chloronaphthalene (TCNE:ClN) in dichloromethane (DCM) is reported with 40 fs time resolution. In the frequency domain, five FSRS peaks are observed with frequencies of 534, 858, 1069, 1392, and 1926 cm-1. The most intense peaks at 534 and 1392 cm-1 correspond to fundamentals while the features at 858, 1069, and 1926 cm-1 are attributed to a difference frequency, an overtone and a combination frequency of the fundamentals, respectively. The frequency of the 1392 cm-1 fundamental corresponding to the central C═C stretch of TCNE•- is red-shifted from the frequency of the steady state radical due to the close proximity and electron affinity of the countercation. The observation of a FSRS band at a difference frequency is analyzed. This analysis lends evidence for alternative nonlinear pathways of inverse Raman gain scattering (IRGS) or vertical-FSRS (VFSRS) which may contribute to the time-evolving FSRS spectrum on-resonance. Impulsive stimulated Raman measurements of the complex show coherent oscillations of the stimulated emission with frequencies of 153, 278, and 534 cm-1. The 278 cm-1 mode corresponds to Cl bending of the dichloromethane solvent. The center frequency of the 278 cm-1 mode is modulated by a frequency of ∼30 cm-1 which is attributed to the effect of librational motion of the dichloromethane solvent as it reorganizes around the nascent contact ion pair. The 153 ± 15 cm-1 mode corresponds to an out-of-plane bending motion of TCNE. This motion modulates the intermolecular separation of the contact ion pair and thereby the overlap of the frontier orbitals which is crucial for rapid charge recombination in 5.9 ± 0.2 ps. High time-frequency resolution vibrational spectra provide unique molecular details regarding charge localization and recombination.

Readiness for Discharge After Foot and Ankle Surgery Using Peripheral Nerve Blocks: A Randomized Controlled Trial Comparing Spinal and General Anesthesia as Supplements to Nerve Blocks.

BACKGROUND: Neuraxial anesthesia is often viewed as superior to general anesthesia but may delay discharge. Comparisons do not typically use multimodal analgesics and nerve blockade. Combining nerve blockade with general anesthesia may reduce pain, opioid consumption, and nausea. We hypothesized that general anesthesia (with nerve blocks) would lead to earlier readiness for discharge, compared to spinal anesthesia (with nerve blocks). METHODS: All patients underwent ambulatory foot and ankle surgery, with a predicted case duration of 1-3 hours. All patients received popliteal and adductor canal nerve blocks using bupivacaine and dexamethasone. No intraoperative opioids were administered. All patients received ondansetron, dexamethasone, ketamine, and ketorolac. Patients, data collectors, and the data analyst were not informed of group assignment. Patients were randomized to spinal or general anesthesia with concealed allocation. Spinal anesthesia was performed with mepivacaine and accompanied with propofol sedation. After general anesthesia was induced with propofol, a laryngeal mask airway was inserted, followed by sevoflurane and propofol. Time until ready for discharge, the primary outcome, was compared between groups after adjusting for age and surgery time using multivariable unconditional quantile regression. Secondary outcomes compared at multiple timepoints were adjusted for multiple comparisons using the Holm-Bonferroni step-down procedure. RESULTS: General anesthesia patients were ready for discharge at a median of 39 minutes earlier (95% confidence interval, 2-75; P = .038) versus spinal anesthesia patients. Patients in both groups met readiness criteria for discharge substantially before actual discharge. Pain scores at rest were higher among general anesthesia patients 1 hour after leaving the operating room (adjusted difference in means, 2.1 [95% confidence interval, 1.0-3.2]; P < .001). Other secondary outcomes (including opioid use, opioid side effects, nausea, headache, sore throat, and back pain) were not different. CONCLUSIONS: General anesthesia was associated with earlier readiness for discharge, but the difference may not be clinically significant and did not lead to earlier actual discharge. Most secondary outcomes were not different between groups. The choice of spinal or general anesthesia as an adjunct to peripheral nerve blockade can reflect patient, clinician, and institutional preferences.