Characteristics associated with effectiveness in postoperative delirium research: a systematic review of randomised controlled trials with meta-regression and meta-analysis.

BACKGROUND: Postoperative delirium remains prevalent despite extensive research through randomised trials aimed at reducing its incidence. Understanding trial characteristics associated with interventions' effectiveness facilitates data interpretation. METHODS: Trial characteristics were extracted from eligible trials identified through two systematic literature searches. Multivariable meta-regression was used to investigate trial characteristics associated with effectiveness estimated using odds ratios. Meta-analysis was used to investigate pooled effectiveness. RESULTS: We identified 201 eligible trials. Compared with China, trials from the USA/Canada (ratio of odds ratio, 1.89; 95% confidence interval, 1.45-2.45) and Europe/Australia/New Zealand (1.67; 1.29-2.18) had an 89% and 67% higher odds ratio, respectively, suggesting reduced effectiveness. The effectiveness was enhanced when the incidence of postoperative delirium increased (0.85; 0.79-0.92, per 10% increase). Trials with concerns related to deviations from intended interventions reported increased effectiveness compared with those at low risk (0.69; 0.53-0.90). Compared with usual care, certain interventions appeared to have reduced the incidence of postoperative delirium in low-risk trials with low-to-moderate certainty of evidence. However, these findings should be considered inconclusive because of challenges in grouping heterogeneous interventions, the limited number of eligible trials, the prevalence of small-scale studies, and potential publication bias. CONCLUSIONS: The effectiveness of postoperative delirium trials varied based on the region of trial origin, the incidence of delirium, and the risk of bias. The limitations caution against drawing definitive conclusions from different bodies of evidence. These findings highlight the imperative need to improve the quality of research on a global scale. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023413984).

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.

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.

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.

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.

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.

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.

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.

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.

Malformation of the Posterior Cerebellar Vermis Is a Common Neuroanatomical Phenotype of Genetically Engineered Mice on the C57BL/6 Background.

C57BL/6 mice exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the posterior vermis, indicative of neuronal migration defect during cerebellar development. Recognizing that many genetically engineered (GE) mouse lines are produced from C57BL/6 ES cells or backcrossed to this strain, we performed histological analyses and found that cerebellar heterotopia were a common feature present in the majority of GE lines on this background. Furthermore, we identify GE mouse lines that will be valuable in the study of cerebellar malformations including diverse driver, reporter, and optogenetic lines. Finally, we discuss the implications that these data have on the use of C57BL/6 mice and GE mice on this background in studies of cerebellar development or as models of disease.

Pain interventions for organ transplant patients undergoing incisional hernia repair: Is epidural or transversus abdominus plane block a better option?

BACKGROUND: Postoperative pain management in transplant recipients undergoing incisional herniorraphy is challenging. Historically limited to intravenous or oral opioids, alternatives including transversus abdominus plane (TAP) block catheters and thoracic epidural catheters have been introduced. The aim of this study was to determine whether TAP catheters and thoracic epidural analgesia significantly impacted on postoperative pain and opioid usage in transplant recipients undergoing incisional hernia repair. METHODS: This single-center retrospective study included 154 patients undergoing incisional hernia repair from January 2011 to June 2015. Of these, 56 received epidurals, 51 received TAP catheters, and 47 received no intervention. RESULTS: Demographic profiles were comparable among the three groups including type of previous transplant and type of hernia surgery. Thoracic epidural analgesia was associated with lower median, mean, and maximum pain scores (P < 0.001) and less opioid requirement (P < 0.001). There was no difference in pain scores and opioid usage among the TAP catheter and no intervention groups. There was no difference in time to first flatus or first bowel movement, length of hospital stay, individual opioid-related side effects, and adverse reactions among the three groups. CONCLUSION: This study supports the use of thoracic epidural analgesia in patients undergoing hernia repair after transplant surgery.

A Cross-Metathesis/Aza-Michael Reaction Strategy for the Synthesis of Cyclic and Bicyclic Ureas.

The synthesis of cyclic and bicyclic ureas via a ruthenium-catalyzed cross-metathesis / aza-Michael reaction strategy between protected alkenyl ureas and Michael acceptors is described. The substrates for these reactions are generated in 1-3 steps from commercially available materials, and products are formed in moderate yield with up to >20:1 diastereoselectivity.

Pd-Catalyzed Alkene Carboheteroarylation Reactions for the Synthesis of 3-Cyclopentylindole Derivatives.

The Pd-catalyzed alkene carboheteroarylation of aryl and alkenyl triflate electrophiles bearing pendant alkenes with heteroaromatic nucleophiles affords substituted carbocycles with 3-indolyl or 3-pyrrolyl groups. The products are obtained in moderate to good yields, and the use of alkenyl triflate substrates produces products with high diastereoselectivities. The transformation is believed to proceed via a Friedel-Crafts-like reaction between the heteroaromatic nucleophile and an intermediate electrophilic palladium complex.

A Case of Metastatic Atypical Neuroendocrine Tumor with ALK Translocation and Diffuse Brain Metastases.

A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well-validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non-small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine-needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52-year-old never-smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed. KEY POINTS: To our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.Second-generation ALK inhibitors represent a new paradigm for treating ALK-positive patients with brain metastases.

Fabrication of multipoint side-firing optical fiber by laser micro-ablation.

A multipoint, side-firing design enables an optical fiber to output light at multiple desired locations along the fiber body. This provides advantages over traditional end-to-end fibers, especially in applications requiring fiber bundles such as brain stimulation or remote sensing. This Letter demonstrates that continuous wave (CW) laser micro-ablation can controllably create conical-shaped cavities, or side windows, for outputting light. The dimensions of these cavities determine the amount of firing light and their firing angle. Experimental data show that a single side window on a 730 µm fiber can deliver more than 8% of the input light. This can be increased to more than 19% on a 65 µm fiber with side windows created using femtosecond laser ablation and chemical etching. Fine control of light distribution along an optical fiber is critical for various biomedical applications such as light-activated drug-release and optogenetics studies.

Stereocontrolled Synthesis of Amino-Substituted Carbocycles by Pd-Catalyzed Alkene Carboamination Reactions.

Amino-substituted alkylidenecyclopentanes were synthesized through a stereoselective intermolecular Pd-catalyzed alkene carboamination reaction between alkenyl triflates bearing a pendant alkene and exogenous amine nucleophiles. The reactions are effective with a range of different substrate combinations, and proceed with generally high diastereoselectivity. Use of (S)-tBuPhox as the ligand in reactions of achiral substrates provides enantioenriched products with up to 98.5:1.5 e.r.

Synthesis of Substituted γ- and δ-Lactams via Pd-Catalyzed Alkene Carboamination Reactions.

The synthesis of substituted γ- and δ-lactams via palladium-catalyzed alkene carboamination reactions between aryl halides and alkenes bearing pendant amides is described. The substrates for these reactions are generated in 1-3 steps from commercially available materials, and products are obtained in good yield with up to >20:1 diastereoselectivity. The stereochemical outcome of the alkene addition is consistent with a mechanism involving anti-aminopalladation of the alkene.

Clinical Improvement of Alpha-mannosidosis Cat Following a Single Cisterna Magna Infusion of AAV1.

Lysosomal storage diseases (LSDs) are debilitating neurometabolic disorders for most of which long-term effective therapies have not been developed. Gene therapy is a potential treatment but a critical barrier to treating the brain is the need for global correction. We tested the efficacy of cisterna magna infusion of adeno-associated virus type 1 (AAV1) expressing feline alpha-mannosidase gene in the postsymptomatic alpha-mannosidosis (AMD) cat, a homologue of the human disease. Lysosomal alpha-mannosidase (MANB) activity in the cerebrospinal fluid (CSF) and serum were increased above the control values in untreated AMD cats. Clinical neurological signs were delayed in onset and reduced in severity. The lifespan of the treated cats was significantly extended. Postmortem histopathology showed resolution of lysosomal storage lesions throughout the brain. MANB activity in brain tissue was significantly above the levels of untreated tissues. The results demonstrate that a single cisterna magna injection of AAV1 into the CSF can mediate widespread neuronal transduction of the brain and meaningful clinical improvement. Thus, cisterna magna gene delivery by AAV1 appears to be a viable strategy for treatment of the whole brain in AMD and should be applicable to many of the neurotropic LSDs as well as other neurogenetic disorders.

Integrated analysis of proteome and transcriptome changes in the mucopolysaccharidosis type VII mouse hippocampus.

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by the deficiency of ß-glucuronidase. In this study, we compared the changes relative to normal littermates in the proteome and transcriptome of the hippocampus in the C57Bl/6 mouse model of MPS VII, which has well-documented histopathological and neurodegenerative changes. A completely different set of significant changes between normal and MPS VII littermates were found in each assay. Nevertheless, the functional annotation terms generated by the two methods showed agreement in many of the processes, which also corresponded to known pathology associated with the disease. Additionally, assay-specific changes were found, which in the proteomic analysis included mitochondria, energy generation, and cytoskeletal differences in the mutant, while the transcriptome differences included immune, vesicular, and extracellular matrix changes. In addition, the transcriptomic changes in the mutant hippocampus were concordant with those in a MPS VII mouse caused by the same mutation but on a different background inbred strain.