Sustained deep-tissue voltage recording using a fast indicator evolved for two-photon microscopy.

Genetically encoded voltage indicators are emerging tools for monitoring voltage dynamics with cell-type specificity. However, current indicators enable a narrow range of applications due to poor performance under two-photon microscopy, a method of choice for deep-tissue recording. To improve indicators, we developed a multiparameter high-throughput platform to optimize voltage indicators for two-photon microscopy. Using this system, we identified JEDI-2P, an indicator that is faster, brighter, and more sensitive and photostable than its predecessors. We demonstrate that JEDI-2P can report light-evoked responses in axonal termini of Drosophila interneurons and the dendrites and somata of amacrine cells of isolated mouse retina. JEDI-2P can also optically record the voltage dynamics of individual cortical neurons in awake behaving mice for more than 30 min using both resonant-scanning and ULoVE random-access microscopy. Finally, ULoVE recording of JEDI-2P can robustly detect spikes at depths exceeding 400 µm and report voltage correlations in pairs of neurons.

Remote control of mechanochemical reactions under physiological conditions using biocompatible focused ultrasound.

External control of chemical reactions in biological settings with spatial and temporal precision is a grand challenge for noninvasive diagnostic and therapeutic applications. While light is a conventional stimulus for remote chemical activation, its penetration is severely attenuated in tissues, which limits biological applicability. On the other hand, ultrasound is a biocompatible remote energy source that is highly penetrant and offers a wide range of functional tunability. Coupling ultrasound to the activation of specific chemical reactions under physiological conditions, however, remains a challenge. Here, we describe a synergistic platform that couples the selective mechanochemical activation of mechanophore-functionalized polymers with biocompatible focused ultrasound (FUS) by leveraging pressure-sensitive gas vesicles (GVs) as acousto-mechanical transducers. The power of this approach is illustrated through the mechanically triggered release of covalently bound fluorogenic and therapeutic cargo molecules from polymers containing a masked 2-furylcarbinol mechanophore. Molecular release occurs selectively in the presence of GVs upon exposure to FUS under physiological conditions. These results showcase the viability of this system for enabling remote control of specific mechanochemical reactions with spatiotemporal precision in biologically relevant settings and demonstrate the translational potential of polymer mechanochemistry.

Smallest Clinically Meaningful Improvement in Amputation-Related Pain and Brief Pain Inventory Scores as Defined by Patient Reports of Global Improvement After Cryoneurolysis: a Retrospective Analysis of a Randomized, Controlled Clinical Trial.

BACKGROUND: The smallest meaningful improvement in pain scores (minimal clinically important difference [MCID]) after an analgesic intervention is essential information when both interpreting published data and designing a clinical trial. However, limited information is available for patients with chronic pain conditions, and what is published is derived from studies involving pharmacologic and psychological interventions. We here calculate these values based on data collected from 144 participants of a previously published multicenter clinical trial investigating the effects of a single treatment with percutaneous cryoneurolysis. METHODS: In the original trial, we enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. At both baseline and 4 months (primary end point), participants rated their phantom limb pain based on a numeric rating scale (NRS) and their interference of pain on physical and emotional functioning as measured with the Brief Pain Inventory's interference subscale. They subsequently qualitatively defined the change using the 7-point ordinal Patient Global Impression of Change (PGIC). The smallest clinically meaningful improvements in phantom limb pain and Brief Pain Inventory scores were calculated using an anchor-based method based on the PGIC. RESULTS: The median (interquartile range [IQR]) phantom pain NRS (0-10) improvements at 4 months considered small, medium, and large were 1 [1-1], 3 [3-4], and 4 [3-6], respectively. The median improvements in the Brief Pain Inventory interference subscale (0-70) associated with a small, medium, and large analgesic changes were 16 [6-18], 24 [22-31], and 34 [22-46]. The proportions of patients that experienced PGIC ≥5 were 33% and 36% in the active and placebo groups, respectively. The relative risk of a patient experiencing PGIC ≥5 in the active group compared to the sham group with 95% confidence interval was 0.9 (0.6-1.4), P = .667. CONCLUSIONS: Amputees with phantom limb pain treated with percutaneous cryoneurolysis rate analgesic improvements as clinically meaningful similar to pharmacologic treatments, although their MCID for the Brief Pain Inventory was somewhat larger than previously published values. This information on patient-defined clinically meaningful improvements will facilitate interpretation of available studies and guide future trial design.

Overwrapping Bivalved Casts: Does the Material Matter?

BACKGROUND: Circumferential integrity of bivalved casts (cut twice longitudinally) can be restored by overwrapping with different materials. This study compared the mechanical properties of solid casts and bivalved casts overwrapped with semirigid fiberglass (SF), elastic bandages (EB), and rigid fiberglass (RF) using an overwrapped-bivalved cast-bone fracture (OBCBF) model. METHODS: This study used an MTS Bionix Servohydraulic system to test properties of OBCBF models in 4 conditions: intact Control made of RF (not bivalved or overwrapped), a Rigid overwrapped model made of a Control bivalved and overwrapped with RF, a Semirigid overwrapped model made of a Control bivalved and overwrapped with SF, and an Elastic model made of a Control bivalved and overwrapped with EB. Constructs were tested in 4-point bending. Force-displacement curves (FDC) were generated to calculate load-at-critical-failure (LCF, angulation > 10 degrees = 6.6 mm vertical deformation) and stiffness. RESULTS: Five controls and 30 OBCBF models with 3 overwrapped cast types were tested, with each overwrapped cast type tested with 2 orientations of the initial cast bivalve axis, yielding 7 conditions (Control, Rigid 0 degrees, Rigid 90 degrees, Semirigid 0 degrees, Semirigid 90 degrees, Elastic 0 degrees, Elastic 90 degrees). Mean LCF was: Rigid 90 degrees > Rigid 0 degrees > Control > Semirigid 0 degrees > Semirigid 90 degrees > Elastic 90 degrees > Elastic 0 degrees (P<0.0001). Mean stiffness was: Rigid 0 degrees > Rigid 90 degrees > Control > Semirigid 90 degrees > Semirigid 0 degrees > Elastic 0 degrees > Elastic 90 degrees (P<0.0001). Multiple comparisons indicated no significant difference between LCF and stiffness for Semirigid 0 degrees/90 degrees casts compared with Controls. CONCLUSIONS: Mechanical properties of overwrapped bivalved casts change depending on the materials used to overwrap, with higher LCF and stiffness when overwrapping with RF > SF > EB; however, mean comparisons indicate that rigid bivalved casts overwrapped with SF did not have significantly different mean stiffness and LCF from controls and other cast models. CLINICAL RELEVANCE: This study compares the bending properties of a bivalved cast-construct overwrapped with different materials, providing basic science evidence for orthopaedic surgeons who have several choices of materials to overwrap bivalved casts.

Selective Near-Infrared Blood Detection Driven by Ionic Liquid-Dye-Albumin Nanointeractions.

Due to its abundance in blood, a great deal of research has been undertaken to develop efficient biosensors for serum albumin and provide insight into the interactions that take place between these biosensing molecules and the protein. Near-infrared (NIR, >700 nm) organic dyes have been shown to be effective biosensors of serum albumin, but their effectiveness is diminished in whole blood. Herein, it is shown that an NIR sulfonate indolizine-donor-based squaraine dye, SO3SQ, can be strengthened as a biosensor of albumin through the addition of biocompatible ionic liquids (ILs). Specifically, the IL choline glycolate (1:1), at a concentration of 160 mM, results in the enhanced fluorescence emission ("switch-on") of the dye in the presence of blood. The origin of the fluorescence enhancement was investigated via methods, including DLS, ITC, and molecular dynamics. Further, fluorescence measurements were conducted to see the impact the dye-IL system had on the fluorescence of the tryptophan residue of human serum albumin (HSA), as well as to determine its apparent association constants in relation to albumin. Circular dichroism (CD) spectroscopy was used to provide evidence that the dye-IL system does not alter the secondary structures of albumin or DNA. Our results suggest that the enhanced fluorescence of the dye in the presence of IL and blood is due to diversification of binding sites in albumin, controlled by the interaction of the IL-dye-albumin complex.

Ultrasound-guided Percutaneous Cryoneurolysis to Treat Chronic Postamputation Phantom Limb Pain: A Multicenter Randomized Controlled Trial.

BACKGROUND: Postamputation phantom pain is notoriously persistent with few validated treatments. Cryoneurolysis involves the application of low temperatures to reversibly ablate peripheral nerves. The authors tested the hypothesis that a single cryoneurolysis treatment would decrease phantom pain 4 months later. METHODS: The authors enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. The primary outcome was the change in average phantom pain intensity between baseline and 4 months as measured with a numeric rating scale (0 to 10), after which an optional crossover treatment was offered. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. RESULTS: Pretreatment phantom pain scores were similar in both groups, with a median [quartiles] of 5.0 [4.0, 6.0] for active treatment and 5.0 [4.0, 7.0] for sham. After 4 months, pain intensity decreased by 0.5 [-0.5, 3.0] in patients given cryoneurolysis (n = 71) versus 0 [0, 3] in patients given sham (n = 73), with an estimated difference (95% CI) of -0.1 (-1.0 to 0.7), P = 0.759. Following their statistical gatekeeping protocol, the authors did not make inferences or draw conclusions on secondary endpoints. One serious adverse event occurred after a protocol deviation in which a femoral nerve cryolesion was induced just below the inguinal ligament-instead of the sensory-only saphenous nerve-which resulted in quadriceps weakness, and possibly a fall and clavicle fracture. CONCLUSIONS: Percutaneous cryoneurolysis did not decrease chronic lower extremity phantom limb pain 4 months after treatment. However, these results were based upon the authors' specific study protocol, and since the optimal cryoneurolysis treatment parameters such as freeze duration and anatomic treatment location remain unknown, further research is warranted.

Acid-Triggered Switchable Near-Infrared/Shortwave Infrared Absorption and Emission of Indolizine-BODIPY Dyes.

Fluorescent organic dyes that absorb and emit in the near-infrared (NIR, 700-1000 nm) and shortwave infrared (SWIR, 1000-1700 nm) regions have the potential to produce noninvasive high-contrast biological images and videos. BODIPY dyes are well known for their high quantum yields in the visible energy region. To tune these chromophores to the NIR region, fused nitrogen-based heterocyclic indolizine donors were added to a BODIPY scaffold. The indolizine BODIPY dyes were synthesized via microwave-assisted Knoevenagel condensation with indolizine aldehydes. The non-protonated dyes showed NIR absorption and emission at longer wavelengths than an aniline benchmark. Protonation of the dyes produced a dramatic 0.35 eV bathochromic shift (230 nm shift from 797 nm to 1027 nm) to give a SWIR absorption and emission (λmaxemis = 1061 nm). Deprotonation demonstrates that material emission is reversibly switchable between the NIR and SWIR.

Guest-Host Raman under Liquid Nitrogen Spectroscopy for the Acquisition of Improved Vibrational Spectra of Solids.

Guest-host Raman under liquid nitrogen spectroscopy (GHRUNS) is introduced whereby solid-state guest molecules are isolated inside cage-like host environments for the facile acquisition of their Raman spectra. This convenient method features reduced fluorescence, the analysis of populations in their ground states, and increased signal to noise ratios. Samples are also preserved through the reduction of thermal degradation and oxidation. To demonstrate the benefits of this new method, Raman spectra of the ubiquitous molecule C60 inside a cage of water ice are presented. Using this technique, a new normal mode of C60 is elucidated. The GHRUNS methodology is of interest to those seeking to acquire and characterize the vibrational spectra, structure, and properties of emissive, air-sensitive molecules.

Ultrasound-Guided Suprazygomatic Nerve Blocks to the Pterygopalatine Fossa: A Safe Procedure.

OBJECTIVES: Large-scale procedural safety data on pterygopalatine fossa nerve blocks (PPFBs) performed via a suprazygomatic, ultrasound-guided approach are lacking, leading to hesitancy surrounding this technique. The aim of this study was to characterize the safety of PPFB. METHODS: This retrospective chart review examined the records of adults who received an ultrasound-guided PPFB between January 1, 2016, and August 30, 2020, at the University of Florida. Indications included surgical procedures and nonsurgical pain. Clinical data describing PPFB were extracted from medical records. Descriptive statistics were calculated for all variables, and quantitative variables were analyzed with the paired t test to detect differences between before and after the procedure. RESULTS: A total of 833 distinct PPFBs were performed on 411 subjects (59% female, mean age 48.5 years). Minor oozing from the injection site was the only reported side effect, in a single subject. Although systolic blood pressure, heart rate, and oxygen saturation were significantly different before and after the procedure (132.3 vs 136.4 mm Hg, P < 0.0001; 78.2 vs 80.8, P = 0.0003; and 97.8% vs 96.3%, P < 0.0001; respectively), mean arterial pressure and diastolic blood pressure were not significantly different (96.2 vs 97.1 mm Hg, P = 0.1545, and 78.2 vs 77.4 mm Hg, P = 0.1314, respectively). Similar results were found within subgroups, including subgroups by sex, race, and indication for PPFB. DISCUSSION: We have not identified clinically significant adverse effects from PPFB performed with an ultrasound-guided suprazygomatic approach in a large cohort in the hospital setting. PPFBs are a safe and well-tolerated pain management strategy; however, prospective multicenter studies are needed.

Assessment of inhalation toxicity of cigarette smoke and aerosols from flavor mixtures: 5-week study in A/J mice.

Most flavors used in e-liquids are generally recognized as safe for oral consumption, but their potential effects when inhaled are not well characterized. In vivo inhalation studies of flavor ingredients in e-liquids are scarce. A structure-based grouping approach was used to select 38 flavor group representatives (FGR) on the basis of known and in silico-predicted toxicological data. These FGRs were combined to create prototype e-liquid formulations and tested against cigarette smoke (CS) in a 5-week inhalation study. Female A/J mice were whole-body exposed for 6 h/day, 5 days/week, for 5 weeks to air, mainstream CS, or aerosols from (1) test formulations containing propylene glycol (PG), vegetable glycerol (VG), nicotine (N; 2% w/w), and flavor (F) mixtures at low (4.6% w/w), medium (9.3% w/w), or high (18.6% w/w) concentration or (2) base formulation (PG/VG/N). Male A/J mice were exposed to air, PG/VG/N, or PG/VG/N/F-high under the same exposure regimen. There were no significant mortality or in-life clinical findings in the treatment groups, with only transient weight loss during the early exposure adaptation period. While exposure to flavor aerosols did not cause notable lung inflammation, it caused only minimal adaptive changes in the larynx and nasal epithelia. In contrast, exposure to CS resulted in lung inflammation and moderate-to-severe changes in the epithelia of the nose, larynx, and trachea. In summary, the study evaluates an approach for assessing the inhalation toxicity potential of flavor mixtures, thereby informing the selection of flavor exposure concentrations (up to 18.6%) for a future chronic inhalation study.

Structural insights into diverse modes of ICAM-1 binding by Plasmodium falciparum-infected erythrocytes.

A major determinant of pathogenicity in malaria caused by Plasmodium falciparum is the adhesion of parasite-infected erythrocytes to the vasculature or tissues of infected individuals. This occludes blood flow, leads to inflammation, and increases parasitemia by reducing spleen-mediated clearance of the parasite. This adhesion is mediated by PfEMP1, a multivariant family of around 60 proteins per parasite genome which interact with specific host receptors. One of the most common of these receptors is intracellular adhesion molecule-1 (ICAM-1), which is bound by 2 distinct groups of PfEMP1, A-type and B or C (BC)-type. Here, we present the structure of a domain from a B-type PfEMP1 bound to ICAM-1, revealing a complex binding site. Comparison with the existing structure of an A-type PfEMP1 bound to ICAM-1 shows that the 2 complexes share a globally similar architecture. However, while the A-type PfEMP1 bind ICAM-1 through a highly conserved binding surface, the BC-type PfEMP1 use a binding site that is more diverse in sequence, similar to how PfEMP1 interact with other human receptors. We also show that A- and BC-type PfEMP1 present ICAM-1 at different angles, perhaps influencing the ability of neighboring PfEMP1 domains to bind additional receptors. This illustrates the deep diversity of the PfEMP1 and demonstrates how variations in a single domain architecture can modulate binding to a specific ligand to control function and facilitate immune evasion.

Diagnostic Value of MAML2 Rearrangements in Mucoepidermoid Carcinoma.

Mucoepidermoid carcinoma (MEC) is often seen in salivary glands and can harbor MAML2 translocations (MAML2+). The translocation status has diagnostic utility as an objective confirmation of the MEC diagnosis, for example, when distinction from the more aggressive adenosquamous carcinoma (ASC) is not straightforward. To assess the diagnostic relevance of MAML2, we examined our 5-year experience in prospective testing of 8106 solid tumors using RNA-seq panel testing in combinations with a two-round Delphi-based scenario survey. The prevalence of MAML2+ across all tumors was 0.28% (n = 23/8106) and the majority of MAML2+ cases were found in head and neck tumors (78.3%), where the overall prevalence was 5.9% (n = 18/307). The sensitivity of MAML2 for MEC was 60% and most cases (80%) were submitted for diagnostic confirmation; in 24% of cases, the MAML2 results changed the working diagnosis. An independent survey of 15 experts showed relative importance indexes of 0.8 and 0.65 for "confirmatory MAML2 testing" in suspected MEC and ASC, respectively. Real-world evidence confirmed that the added value of MAML2 is a composite of an imperfect confirmation test for MEC and a highly specific exclusion tool for the diagnosis of ASC. Real-world evidence can help move a rare molecular-genetic biomarker from an emerging tool to the clinic.

Shortwave Infrared Absorptive and Emissive Pentamethine-Bridged Indolizine Cyanine Dyes.

Shortwave infrared (SWIR)-emitting small molecules are desirable for biological imaging applications. In this study, four novel pentamethine indolizine cyanine dyes were synthesized with N,N-dimethylaniline-based substituents on the indolizine periphery at varied substitution sites. The dyes are studied via computational chemistry and optical spectroscopy both in solution and when encapsulated. Dramatic spectral shifts in the absorption and emission spectrum wavelengths with added donor groups are observed. Significant absorption and emission with an emissive quantum yield as high as 3.6% in the SWIR region is possible through the addition of multiple donor groups per indolizine.

Pterygopalatine Fossa Blockade as Novel, Narcotic-Sparing Treatment for Headache in Patients with Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: Severe headache is a hallmark clinical feature of spontaneous subarachnoid hemorrhage (SAH), affecting nearly 90% of patients during index hospitalization, regardless of the SAH severity or presence of a culprit aneurysm. Up to 1 in 4 survivors of SAH experience chronic headaches, which may be severe and last for years. Data guiding the optimal management of post-SAH headache are lacking. Opioids, often in escalating doses, remain the guideline-recommended mainstay of acute therapy, but pain relief remains suboptimal. METHODS: This study is a case series of adult patients who received bilateral pterygopalatine fossa (PPF) blockade for the management of refractory headaches after spontaneous SAH (aneurysmal and non-aneurysmal) at a single tertiary care center. We examined pain scores and analgesic requirements before and after block placement. RESULTS: Seven patients (median age 54 years, 3 men, four aneurysmal and three non-aneurysmal) received a PPF-block between post-bleed day 6-11 during index hospitalization in the neurointensive care unit. The worst pain recorded in the 24-h period before the block was significantly higher than in the period 4 h after the block (9.1 vs. 3.1; p = 0.0156), and in the period 8 h after the block (9.1 vs. 2.8; p = 0.0313). The only complication was minor oozing from the needle insertion sites, which subsided completely with gauze pressure within 1 min. CONCLUSIONS: PPF blockade might constitute a promising opioid-sparing therapeutic strategy for the management of post-SAH headache that merits further prospective controlled randomized studies.

NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products.

Peptide and protein drug molecules fold into higher order structures (HOS) in formulation and these folded structures are often critical for drug efficacy and safety. Generic or biosimilar drug products (DPs) need to show similar HOS to the reference product. The solution NMR spectroscopy is a non-invasive, chemically and structurally specific analytical method that is ideal for characterizing protein therapeutics in formulation. However, only limited NMR studies have been performed directly on marketed DPs and questions remain on how to quantitively define similarity. Here, NMR spectra were collected on marketed peptide and protein DPs, including calcitonin-salmon, liraglutide, teriparatide, exenatide, insulin glargine and rituximab. The 1D 1H spectral pattern readily revealed protein HOS heterogeneity, exchange and oligomerization in the different formulations. Principal component analysis (PCA) applied to two rituximab DPs showed consistent results with the previously demonstrated similarity metrics of Mahalanobis distance (DM) of 3.3. The 2D 1H-13C HSQC spectral comparison of insulin glargine DPs provided similarity metrics for chemical shift difference (Δδ) and methyl peak profile, i.e., 4 ppb for 1H, 15 ppb for 13C and 98% peaks with equivalent peak height. Finally, 2D 1H-15N sofast HMQC was demonstrated as a sensitive method for comparison of small protein HOS. The application of NMR procedures and chemometric analysis on therapeutic proteins offer quantitative similarity assessments of DPs with practically achievable similarity metrics.

Kinetics and Thermodynamics of Reactions Involving Criegee Intermediates: An Assessment of Density Functional Theory and Ab Initio Methods Through Comparison with CCSDT(Q)/CBS Data.

Reactions involving Criegee intermediates (CIs, R1 R2 COO) are important in atmospheric ozonolysis models. In recent years, density functional theory (DFT) and CCSD(T)-based ab initio methods are increasingly being used for modeling reaction profiles involving CIs. We obtain highly accurate CCSDT(Q)/CBS reaction energies and barrier heights for ring-closing reactions involving atmospherically important CIs (R1 /R2 = H, Me, OH, OMe, F, CN, cyclopropene, ethylene, acetaldehyde, and acrolein). We use this benchmark data to evaluate the performance of DFT, double-hybrid DFT (DHDFT), and ab initio methods for the kinetics and thermodynamics of these reactions. We find that reaction energies are more challenging for approximate theoretical procedures than barrier heights. Overall, taking both reaction energies and barrier heights into account, only one of the 58 considered DFT methods (the meta-GGA MN12-L) attains near chemical accuracy, with root-mean-square deviations (RMSDs) of 3.5 (barrier heights) and 4.7 (reaction energies) kJ mol-1 . Therefore, MN12-L is recommended for investigations where CCSD(T)-based methods are not computationally feasible. For reaction barrier heights performance does not strictly follow Jacob's Ladder, for example, DHDFT methods do not perform better than conventional DFT methods. Of the ab initio methods, the cost-effective CCSD(T)/CBS(MP2) approach gives the best performance for both reaction energies and barrier heights, with RMSDs of 1.7 and 1.4 kJ mol-1 , respectively. All the considered Gaussian-n methods show good performance with RMSDs below the threshold of chemical accuracy for both reaction energies and barrier heights, where G4(MP2) shows the best overall performance with RMSDs of 2.9 and 1.5 kJ mol-1 , respectively. © 2019 Wiley Periodicals, Inc.

Evaluating Donor Effects in Isoindigo-Based Small Molecular Fluorophores.

Small molecular organic fluorophores have garnered significant interest because of their indispensable use in fluorescence imaging (FI) and optoelectronic devices. Herein, we designed triphenylamine (TPA)-capped donor-acceptor-donor (D-A-D)-based fluorophores having a variation at the heterocyclic donor (D) units, 3,4-ethylenedioxythiophene (EDOT), furan (FURAN), thiophene (THIO), and 1-methyl-1H-pyrrole (MePyr), with isoindigo as the core electron acceptor (A) unit. Synthesis of these fluorophores (II-X-TPA) resulted in four symmetrical dye molecules: II-EDOT-TPA, II-FURAN-TPA, II-THIO-TPA, and II-MePyr-TPA, where TPA functioned as a terminal unit and a secondary electron donor group. Photophysical, electrochemical, and computational analyses were conducted to investigate the effect of heterocyclic donor units on the II-X-TPA derivatives. Density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations provided insightful features of structural and electronic properties of each fluorophore and correlated well with experimental observations. Electron density distribution maps, overlapping frontier molecular orbital diagrams, and highest occupied molecular orbital (HOMO) to lowest unoccupied molecular orbital (LUMO) electron transfer indicated intramolecular charge transfer (ICT). Theoretical studies confirmed the experimental HOMO energy trend and demonstrated its crucial importance in understanding each heterocycle's donor ability. Stokes shifts of up to ∼178 nm were observed, whereas absorptions and emissions were shifted deeper into the NIR region, resulting from ICT. Results suggest that this isoindigo fluorophore series has potential as a molecular scaffold for the development of efficient FI agents. The studied fluorophores can be further tuned with different donor fragments to enhance the ICT and facilitate in shifting the optical properties further into the NIR region.

Trigeminal Nerve Blockade in the Pterygopalatine Fossa for the Management of Postoperative Pain in Three Adults Undergoing Tonsillectomy: A Proof-of-Concept Report.

SETTING: Post-tonsillectomy pain in adults can be severe and is often poorly controlled. Pain can lead to decreased oral intake, bleeding, longer hospital stays, emergency department visits, dehydration, and weight loss. Due to persistent pain despite scheduled medications, other methods for pain control are needed. Local/regional anesthetic options have been previously studied in this population. Unfortunately, neither the injection of local anesthetics into the tonsillar fossa nor the postoperative topical application of local anesthetics to the tonsillar bed has demonstrated efficacy in large systematic reviews. PATIENTS: Here we report on the post-tonsillectomy pain experience of three patients who were treated with perioperative nerve blocks placed in the pterygopalatine fossa. This represents an as-yet unexplored option for post-tonsillectomy pain control. INTERVENTION: After induction of general anesthesia, before surgical incision, a 25-gauge spinal needle was advanced into the pterygopalatine fossa using a suprazygomatic, ultrasound-guided approach. Ropivacaine and dexamethasone were deposited into the pterygopalatine fossa. RESULTS: All three patients experienced excellent pain control for the duration of their recovery and required ≤10 mg of oxycodone over the two weeks after surgery. CONCLUSIONS: Our case series of three patients provides proof of concept that use of nerve blocks in the pterygopalatine fossa can be useful for the control of post-tonsillectomy pain. Further study is needed to confirm these initial results.

Rightward directional bias in art produced by cultures without a written language.

In this study, we coded art painted on rocks located in southern Africa, which was painted with a mixture of ochre, blood, and clay by the San, a Neolithic culture with no written language. These images depict a mixture of humans and animals in a variety of contexts, including (but not limited to) hunts and dances. We calculated a laterality index for the collected available art from each region, finding that although there was variability across regions in the direction of the laterality scores, most regions contained a majority of figures facing rightward. This is in stark contrast with reports of artists drawing leftward facing animals and human profiles (an effect that is influenced by native language writing system direction, gender, and handedness), but interestingly our sample also contained regions with strong leftward biases. Our results are, however, in accord with studies that report people preferring images that depict left-to-right motion, as well as the left-to-right bias in depicting transitive actions, an effect that seems to result from greater right hemispheric activation in scene processing and interpretation. Thus, this study shows that in the absence of a writing system, right-lateralized neural architecture may guide the hands of artists.

A cognitive transition underlying both technological and social aspects of cumulative culture.

The argument that cumulative technological culture originates in technical-reasoning skills is not the only alternative to social accounts; another possibility is that accumulation of both technical-reasoning skills and enhanced social skills stemmed from the onset of a more basic cognitive ability such as recursive representational redescription. The paper confuses individual learning of pre-existing information with creative generation of new information.