Synthesis of Biindene Derivatives via Pd-Catalyzed Alkene Difunctionalization Reactions.

The palladium-catalyzed cross-coupling of 2-allylphenyl triflate and related electrophiles with substituted indenes affords biindene derivatives in moderate to good yields with high selectivity for thermodynamically preferred alkene isomers. The transformations involve alkene nucleopalladation with indenyl anions, and we also demonstrate that 2-allylphenyl triflates can be transformed to indenes under similar conditions. The scope of this transformation, along with the mechanism of formation of both indene and biindene products, is described.

Influence of CUREs on STEM retention depends on demographic identities.

Research has shown that undergraduate research experiences can have substantive effects on retaining students in science, technology, engineering and mathematics (STEM). However, it is impossible to provide individual research experiences for every undergraduate student, especially at large universities. Course-based undergraduate research experiences (CUREs) have become a common approach to introduce large numbers of students to research. We investigated whether a one-semester CURE that replaced a traditional introductory biology laboratory course could increase retention in STEM as well as intention to remain in STEM, if the results differed according to demography, and investigated the possible motivational factors that might mediate such an effect. Under the umbrella of the Authentic Research Connection (ARC) program, we used institutional and survey data from nine semesters and compared ARC participants to non-participants, who applied to ARC but either were not randomly selected or were selected but chose not to enroll in an ARC section. We found that ARC had significant effects on demographic groups historically less likely to be retained in STEM: ARC participation resulted in narrowing the gaps in graduation rates in STEM (first vs continuing-generation college students) and in intention to major in STEM [females vs males, Persons Excluded because of Ethnicity or Race (PEERs) vs non-PEERs]. These disproportionate boosts in intending STEM majors among ARC students coincide with their reporting a greater sense of student cohesiveness, retaining more interest in biology, and commenting more frequently that the course provided a useful/valuable learning experience. Our results indicate that CUREs can be a valuable tool for eliminating inequities in STEM participation, and we make several recommendations for further research.

The Role of Regional Anaesthesia and Acute Pain Services in Value-Based Healthcare.

Value-based healthcare prioritizes patient outcomes and quality relative to costs, shifting focus from service volume to delivered value. This review explores the significant role of regional anaesthesia (RA) and acute pain services (APS) within the evolving value-based healthcare (VBHC) framework. At the heart of VBHC is the goal to enhance patient outcomes while simultaneously optimizing operational efficiency and reducing costs. The review underscores the need for VBHC and illustrates how integrating RA/APS with Enhanced Recovery Protocols can lead to improved outcomes, aligning directly with the goals of the Triple Aim. Several clinical studies show that RA improves patient outcomes, enhances operating room efficiency, and reduces costs. This is complemented by a discussion on the integration of RA and APS into the VBHC model, highlighting emerging value-based payment structures and strategies for their successful implementation. By merging specialized RA/APS protocols with standardized clinical practices, significant improvements in operating room efficiency and associated economic benefits are observed. Across the healthcare spectrum, from providers to payers, this synergy results in enhanced operational efficiency and communication, raising the standard of patient care. Additionally, the potential of RA and APS to address the opioid crisis, through alternative pain management methods, is emphasized. Globally, the shift towards VBHC requires international collaboration, sharing of best practices, and efficient resource allocation, with RA and APS playing a crucial role. In conclusion, as healthcare moves toward a value-driven model, RA and APS become increasingly essential, signaling a future of refined, patient-centered care.

Palladium-Catalyzed Synthesis of 1-Alkylidene-2-dialkylaminomethyl Cyclobutane Derivatives via Pd-Catalyzed Alkene Difunctionalization Reactions: Influence of Nucleophile and Water on the Reaction Mechanism.

The Pd-catalyzed coupling of 1,5-diene-2-yl triflates with amine nucleophiles affords exomethylenecyclobutanes bearing dialkylaminomethyl groups at C2. The strained carbocyclic products are obtained in moderate to excellent yields, with regioselectivities of up to >95:5 for four-membered ring formation. The mechanism of these reactions, which provides products resulting from anti-addition to alkenes, differs from related reactions involving malonate nucleophiles that provide syn-addition products.

Synthesis of 2-Cyanomethyl Indane Derivatives via Pd-Catalyzed Alkene Difunctionalization Reactions of Alkyl Nitriles.

The synthesis of indanes bearing substituted cyanomethyl groups at C2 is achieved through Pd-catalyzed coupling reactions between 2-allylphenyl triflate derivatives and alkyl nitriles. Related partially saturated analogues were generated from analogous transformations of alkenyl triflates. The use of a preformed BrettPhosPd(allyl)(Cl) complex as a precatalyst was essential for the success of these reactions.

Regiodivergent Palladium-Catalyzed Alkene Difunctionalization Reactions for the Construction of Methylene Cyclobutanes and Methylene Cyclopentanes.

Regiodivergent palladium-catalyzed alkene difunctionalization reactions between diethyl malonate and 1,5-dienes bearing a triflate group at C2 are described. Use of tris(2,4-di-tert-butylphenyl)phosphite as a ligand leads to 4-exo-cyclization/functionalization to afford malonate-substituted methylene cyclobutanes. In contrast, the 1,2-bis(diphenylphosphino)benzene ligand provides methylene cyclopentanes via 5-endo-cyclization/functionalization. The five-membered ring-forming reactions occur via anti-carbopalladation of the enolate nucleophile, whereas four-membered ring-forming reactions proceed through syn-4-exo-migratory insertion of the tethered alkene, followed by C(sp3)-C(sp3) bond-forming reductive elimination from an (alkyl)Pd(II)(malonate) complex.

Transduction characteristics of alternative adeno-associated virus serotypes in the cat brain by intracisternal delivery.

Multiple studies have examined the transduction characteristics of different AAV serotypes in the mouse brain, where they can exhibit significantly different patterns of transduction. The pattern of transduction also varies with the route of administration. Much less information exists for the transduction characteristics in large-brained animals. Large animal models have brains that are closer in size and organization to the human brain, such as being gyrencephalic compared to the lissencephalic rodent brains, pathway organization, and certain electrophysiologic properties. Large animal models are used as translational intermediates to develop gene therapies to treat human diseases. Various AAV serotypes and routes of delivery have been used to study the correction of pathology in the brain in lysosomal storage diseases. In this study, we evaluated the ability of selected AAV serotypes to transduce cells in the cat brain when delivered into the cerebrospinal fluid via the cisterna magna. We previously showed that AAV1 transduced significantly greater numbers of cells than AAV9 in the cat brain by this route. In the present study, we evaluated serotypes closely related to AAVs 1 and 9 (AAVs 6, AS, hu32) that may mediate more extensive transduction, as well as AAVs 4 and 5, which primarily transduce choroid plexus epithelial (CPE) and ependymal lining cells in the rodent brain. The related serotypes tended to have similar patterns of transduction but were divergent in some specific brain structures.

Systemic immunosuppression promotes survival and integration of subretinally implanted human ESC-derived photoreceptor precursors in dogs.

Regenerative therapies aimed at replacing photoreceptors are a promising approach for the treatment of otherwise incurable causes of blindness. However, such therapies still face significant hurdles, including the need to improve subretinal delivery and long-term survival rate of transplanted cells, and promote sufficient integration into the host retina. Here, we successfully delivered in vitro-derived human photoreceptor precursor cells (PRPCs; also known as immature photoreceptors) to the subretinal space of seven normal and three rcd1/PDE6B mutant dogs with advanced inherited retinal degeneration. Notably, while these xenografts were rejected in dogs that were not immunosuppressed, transplants in most dogs receiving systemic immunosuppression survived up to 3-5 months postinjection. Moreover, differentiation of donor PRPCs into photoreceptors with synaptic pedicle-like structures that established contact with second-order neurons was enhanced in rcd1/PDE6B mutant dogs. Together, our findings set the stage for evaluating functional vision restoration following photoreceptor replacement in canine models of inherited retinal degeneration.

Liposomal bupivacaine addition versus standard bupivacaine alone for colorectal surgery: a randomized controlled trial.

Aim: This study evaluated use of liposomal bupivacaine (LB) versus standard bupivacaine (SB) alone in quadratus lumborum (QL) blocks for laparoscopic colorectal surgery. Materials & methods: In this prospective, randomized controlled trial, patients received QL1 blocks with either LB (40 ml 0.125% SB plus 20 ml of LB) or SB (60 ml of 0.25% SB) with 30 ml per side. Opioid usage, pain scores, side effects and other medications were recorded. Results: For 78 patients (38 LB; 40 SB), all parameters were similar between groups, except that the LB group had a higher 48 h need for metoclopramide. Conclusion: LB provided no analgesic benefit over SB alone for QL blocks. Clinical Trials registration number: NCT03702621.

Lay abstract This study evaluated use of extended release bupivacaine (LB) versus standard bupivacaine (SB) alone in nerve blocks for laparoscopic colorectal surgery. Patients undergoing colorectal surgery received nerve blocks with either LB combined with SB, or SB alone. Opioid usage, pain scores, side effects and other medications were recorded. For 78 patients (38 LB + SB; 40 SB), all parameters were similar between groups, except that the LB group had a higher 48 h need for anti-nausea medication. LB provided no pain control benefit over SB alone for nerve blocks in colorectal surgery.

A Novel Use of Laryngoscope for Difficult Papanicolaou Smear Collection.

The prevalence of cervical cancer has dropped significantly since introduction of the Papanicolaou (Pap) screen. The greatest risk factor for cervical cancer is inadequate screening. Altered pelvic anatomy can limit the ability to collect a Pap smear. In the presented case, a woman with a history of fibroids and bleeding presented for an exam under anesthesia. Traditional approaches for collecting a Pap smear failed. A GlideScope video laryngoscope was used to visualize the cervix, and a Pap smear was collected. The specimen was satisfactory, negative for intraepithelial lesion or malignancy, and HPV negative. A laryngoscope can be repurposed to visualize collection of a challenging Pap smear. Novel approaches for Pap smear collection and cervical cancer screening are needed and have the potential to save lives.

Pd-Catalyzed Alkene Diamination Reactions with O-Benzoylhydroxylamine Electrophiles: Evidence Supporting a Pd(II/IV) Catalytic Cycle, the Role of 2,4-Pentanedione Derivatives as Ligands, and Expanded Substrate Scope.

This article describes continued studies on Pd-catalyzed alkene diamination reactions between N-allylguanidines or ureas and O-benzoylhydroxylamine derivatives, which serve as N-centered electrophiles. The transformations generate cyclic guanidines and ureas bearing dialkylaminomethyl groups in moderate to good yield. We describe new mechanistic experiments that have led to a revised mechanistic hypothesis that involves a key oxidative addition of the electrophile to a PdII complex, followed by reductive elimination from PdIV to form the alkyl carbon-nitrogen bond. In addition, we demonstrate that acac, not phosphine, serves as a key ligand for palladium. Moreover, simple acac derivatives bearing substituted aryl groups outperform acac in the catalytic reactions, and phosphines inhibit catalysis in many cases. These discoveries have led to a significant expansion in the scope of this chemistry, which now allows for the coupling of a variety of cyclic amines, acyclic secondary amines, and primary amines. In addition, we also demonstrate that these new conditions allow for the use of amide nucleophiles, in addition to guanidines and ureas.

Islet1 Precursors Contribute to Mature Interneuron Subtypes in Mouse Neocortex.

Cortical interneurons (GABAergic cells) arise during embryogenesis primarily from the medial and caudal ganglionic eminences (MGE and CGE, respectively) with a small population generated from the preoptic area (POA). Progenitors from the lateral ganglionic eminence (LGE) are thought to only generate GABAergic medium spiny neurons that populate the striatum and project to the globus pallidus. Here, we report evidence that neuronal precursors that express the LGE-specific transcription factor Islet1 (Isl1) can give rise to a small population of cortical interneurons. Lineage tracing and homozygous deletion of Nkx2.1 in Isl1 fate-mapped mice showed that neighboring MGE/POA-specific Nkx2.1 cells and LGE-specific Isl1 cells make both common and distinct lineal contributions towards cortical interneuron fate. Although the majority of cells had overlapping transcriptional domains between Nkx2.1 and Isl1, a population of Isl1-only derived cells also contributed to the adult cerebral cortex. The data indicate that Isl1-derived cells may originate from both the LGE and the adjacent LGE/MGE boundary regions to generate diverse neuronal progeny. Thus, a small population of neocortical interneurons appear to originate from Isl-1-positive precursors.

Effect of Prior Formal Education on Successful Thoracic Epidural Placement By Anesthesia Residents.

OBJECTIVE: Catheter placement for thoracic epidural analgesia (TEA) is technically challenging; however, methods for teaching this technique to anesthesia residents have not been well-studied. The present study aimed to determine optimal teaching methods for proficient TEA catheter placement by comparing video-based formal resident education with traditional bedside training by attending physicians. DESIGN: Prospective, randomized study. SETTING: Large academic hospital, single institution. PARTICIPANTS: The study comprised 76 postgraduate year 3 and 4 anesthesiology residents (38 intervention, 38 control). INTERVENTIONS: Formal education included an instructional video on proper TEA technique. MEASUREMENTS AND MAIN RESULTS: Measures of proficiency in TEA catheter placement included the time needed to complete the procedure successfully and the success of placement as indicated by patient confirmation. Residents who received formal video instruction had similar success in catheter placement and similar procedure times compared with the traditionally trained residents. The overall success rate was 99.2%, with faculty intervention required in only 17% of cases. More experienced residents (ie, having placed more epidural catheters) were faster at TEA catheter placement. CONCLUSIONS: Formal video education for TEA catheter placement provided no additional improvement of resident proficiency compared with traditional training at a high-volume academic center. The success rate was very high in this group of residents; however, experiences at other institutions may vary. Future studies are needed to determine optimum teaching strategies for TEA.

Global CNS correction in a large brain model of human alpha-mannosidosis by intravascular gene therapy.

Intravascular injection of certain adeno-associated virus vector serotypes can cross the blood-brain barrier to deliver a gene into the CNS. However, gene distribution has been much more limited within the brains of large animals compared to rodents, rendering this approach suboptimal for treatment of the global brain lesions present in most human neurogenetic diseases. The most commonly used serotype in animal and human studies is 9, which also has the property of being transported via axonal pathways to distal neurons. A small number of other serotypes share this property, three of which were tested intravenously in mice compared to 9. Serotype hu.11 transduced fewer cells in the brain than 9, rh8 was similar to 9, but hu.32 mediated substantially greater transduction than the others throughout the mouse brain. To evaluate the potential for therapeutic application of the hu.32 serotype in a gyrencephalic brain of larger mammals, a hu.32 vector expressing the green fluorescent protein reporter gene was evaluated in the cat. Transduction was widely distributed in the cat brain, including in the cerebral cortex, an important target since mental retardation is an important component of many of the human neurogenetic diseases. The therapeutic potential of a hu.32 serotype vector was evaluated in the cat homologue of the human lysosomal storage disease alpha-mannosidosis, which has globally distributed lysosomal storage lesions in the brain. Treated alpha-mannosidosis cats had reduced severity of neurological signs and extended life spans compared to untreated cats. The extent of therapy was dose dependent and intra-arterial injection was more effective than intravenous delivery. Pre-mortem, non-invasive magnetic resonance spectroscopy and diffusion tensor imaging detected differences between the low and high doses, and showed normalization of grey and white matter imaging parameters at the higher dose. The imaging analysis was corroborated by post-mortem histological analysis, which showed reversal of histopathology throughout the brain with the high dose, intra-arterial treatment. The hu.32 serotype would appear to provide a significant advantage for effective treatment of the gyrencephalic brain by systemic adeno-associated virus delivery in human neurological diseases with widespread brain lesions.

Transversus abdominis plane (TAP) block for laparoscopic live donor nephrectomy: Continuous catheter infusion provides no additional analgesic benefit over single-injection ropivacaine.

BACKGROUND: Transversus abdominis plane (TAP) blocks are useful for adjunctive pain control following laparoscopic live donor nephrectomy (LLDN). The objective was to determine if TAP catheter provides additional analgesia compared with single-injection TAP block alone for kidney donors. METHODS: In this prospective, double-blinded, randomized controlled trial, LLDN patients received a single TAP injection of 30 mL 0.2% ropivacaine and had a catheter inserted into the TAP space. Postoperatively, either 0.2% ropivacaine (TAP catheter group; TAP-C) or saline (TAP saline group; TAP-S) was infused at 10 mL/h. Pain scores, narcotic usage, nausea, and sedation were evaluated at 1, 12, 24, 36, 48, and 60 hours. RESULTS: The study population included 70 patients (35 randomly assigned to each group). No differences in pain scores, narcotic usage, nausea, or sedation were observed at any time point (with the exception of lower median pain score for TAP-S at 60 hours; 3.2 vs 3.9 for TAP-C; P = .03). CONCLUSIONS: The lower pain score for placebo group at 60-hour postoperative is likely clinically insignificant. The TAP catheter infusion provided no benefit over a single-injection TAP block; thus, the added risk and cost are not supported. Liposomal bupivacaine should be evaluated in future studies.

Randomized Prospective Study Evaluating Single-Injection Paravertebral Block, Paravertebral Catheter, and Thoracic Epidural Catheter for Postoperative Regional Analgesia After Video-Assisted Thoracoscopic Surgery.

OBJECTIVE: Video-assisted thoracoscopic surgery (VATS) has improved patient outcomes; however, postoperative pain remains potentially severe. The objective of this study was to compare adjunct analgesic modalities for VATS, including paravertebral nerve blockade (PVB) and thoracic epidural anesthesia (TEA). DESIGN: Prospective, randomized trial. SETTING: Large academic hospital, single institution. PARTICIPANTS: Adult patients undergoing VATS. INTERVENTIONS: Ultrasound-guided PVB catheter, ultrasound-guided single-injection PVB, or TEA. MEASUREMENTS AND MAIN RESULTS: Postoperative visual analog scale pain scores (at rest and with knee flexion) and opioid usage were recorded. Pain scores (with movement) for the TEA group were lower than those for either PVB group at 24 hours (p ≤ 0.008) and for the PVB catheter group at 48 hours (p = 0.002). Opioid use in TEA group was lower than that for either PVB group at 24 and 48 hours (p < 0.001) and 72 hours (p < 0.05). Single-injection PVB was faster compared with PVB catheter placement (6 min v 12 min; p < 0.001) but similar to TEA (5 min). Patient satisfaction, nausea, sedation, and 6-month postsurgical pain did not differ between groups. CONCLUSIONS: TEA led to lower pain scores and opioid requirement for VATS procedures compared with PVB techniques. Single-injection PVB was faster and equally as effective as PVB catheter, and it led to similar patient satisfaction as TEA; therefore, it should be considered in patients who are not ideal candidates for TEA.

Pd-Catalyzed C-C, C-N, and C-O Bond-Forming Difunctionalization Reactions of Alkenes Bearing Tethered Aryl/Alkenyl Triflates.

Over the past few years our group has described a new type of alkene difunctionalization reaction in which aryl or alkenyl triflates bearing tethered alkenes are coupled with various nucleophiles to afford carbocyclic products. The products are formed in moderate to good chemical yield, with generally high levels of stereoselectivity. Our progress to date in this area, which includes reactions of amine, alcohol, enolate, and indole nucleophiles, is described in this review.

Stereocontrolled synthesis of bicyclic ureas and sulfamides via Pd-catalyzed alkene carboamination reactions.

The synthesis of bicyclic ureas and sulfamides via palladium-catalyzed alkene carboamination reactions between aryl/alkenyl halides/triflates and alkenes bearing pendant cyclic sulfamides and ureas is described. The substrates for these reactions are generated in 3-5 steps from commercially available materials, and products are obtained in good yield with up to >20:1 diastereoselectivity. The stereochemical outcome of the sulfamide alkene addition is consistent with a mechanism involving anti-aminopalladation of the alkene, whereas the stereochemical outcome of the urea alkene addition is consistent with a syn-aminopalladation mechanism.

Comparison of methods of providing analgesia after pancreas transplant: IV opioid analgesia versus transversus abdominis plane block with liposomal bupivacaine or continuous catheter infusion.

BACKGROUND: Current practices emphasize a multimodal approach to perioperative analgesia due to higher efficacy and decreased opioid usage. Analgesia for pancreas transplant (PT) has traditionally been managed with intravenous (IV) opioids, and reports of transversus abdominis plane (TAP) blocks are limited in this population. METHODS: Three interventions were compared in adult PT patients, including IV opioids, TAP catheter, and TAP block with liposomal bupivacaine. Time to return of intestinal function and oral diet, postoperative pain scores, opioid usage, and length of stay were recorded. RESULTS: Study included 197 PT patients: 62 (32%) standard care, 90 (45%) TAP catheters with continuous 0.2% ropivacaine, and 45 (23%) single liposomal bupivacaine TAP block. Pain scores were lowest for the IV opioid group (P < 0.001). The liposomal bupivacaine group had lower pain scores on postoperative days (POD) 1-5 than the TAP catheter group. Opioid use during POD 1-5 was lower for both TAP block groups (P = 0.03). Time to bowel function was faster for the TAP block groups (P < 0.05). CONCLUSIONS: Compared with IV opioid analgesia, TAP block interventions were associated with lower overall use of opioids and a faster time to intestinal function following pancreas transplant.

Pd-Catalyzed Alkene Difunctionalization Reactions of Malonate Nucleophiles: Synthesis of Substituted Cyclopentanes via Alkene Aryl-Alkylation and Akenyl-Alkylation.

The Pd-catalyzed coupling of malonate nucleophiles with alkenes bearing tethered aryl or alkenyl triflates is described. These alkene difunctionalization reactions afford malonate-substituted cyclopentanes that contain fused aryl or cycloalkenyl rings. The transformations generate a five-membered ring, two C-C bonds, and provide products bearing up to three stereocenters with good chemical yield and generally high diastereoselectivity.