Scoping Review: Anesthesiologist Involvement in Alternative Payment Models, Value Measurement, and Nonclinical Capabilities for Success in the United States of America.

The US healthcare sector is undergoing significant payment reforms, leading to the emergence of Alternative Payment Models (APMs) aimed at improving clinical outcomes and patient experiences while reducing costs. This scoping review provides an overview of the involvement of anesthesiologists in APMs as found in published literature. It specifically aims to categorize and understand the breadth and depth of their participation, revolving around 3 main axes or "Aims": (1) shaping APMs through design and implementation, (2) gauging the value and quality of care provided by anesthesiologists within these models, and (3) enhancing nonclinical abilities of anesthesiologists for promoting more value in care. To map out the existing literature, a comprehensive search of relevant electronic databases was conducted, yielding a total of 2173 articles, of which 24 met the inclusion criteria, comprising 21 prospective or retrospective cohort studies, 2 surveys, and 1 case-control cohort study. Eleven publications (45%) discussed value-based, bundled, or episode-based payments, whereas the rest discussed non-payment-based models, such as Enhanced Recovery After Surgery (7 articles, 29%), Perioperative Surgical Home (4 articles, 17%), or other models (3 articles, 13%).The review identified key themes related to each aim. The most prominent themes for aim 1 included protocol standardization (16 articles, 67%), design and implementation leadership (8 articles, 33%), multidisciplinary collaboration (7 articles, 29%), and role expansion (5 articles, 21%). For aim 2, the common themes were Process-Based & Patient-Centric Metrics (1 article, 4%), Shared Accountability (3 articles, 13%), and Time-Driven Activity-Based Costing (TDABC) (3 articles, 13%). Furthermore, we identified a wide range of quality metrics, spanning 8 domains that were used in these studies to evaluate anesthesiologists' performance. For aim 3, the main extracted themes included Education on Healthcare Transformation and Policies (3 articles, 13%), Exploring Collaborative Leadership Skills (5 articles, 21%), and Embracing Advanced Analytics and Data Transparency (4 articles, 17%).Findings revealed the pivotal role of anesthesiologists in the design, implementation, and refinement of these emerging delivery and payment models. Our results highlight that while payment models are shifting toward value, patient-centered metrics have yet to be widely accepted for use in measuring quality and affecting payment for anesthesiologists. Gaps remain in understanding how anesthesiologists assess their direct impact and strategies for enhancing the sustainability of anesthesia practices. This review underscores the need for future research contributing to the successful adaptation of clinical practices in this new era of healthcare delivery.

Human dissection for anesthesiology resident training augments anatomical knowledge and clinical skills.

Anatomy is an essential component of clinical anesthesiology. The use of simulated patients and alternative materials, including embalmed human bodies, have become increasingly common during resident physician training due to the deemphasis on anatomical education during undergraduate medical training. In this report, the need for a more extensive review of relevant anatomy for the practice of anesthesiology was addressed by the design, evaluation, and dissemination of a human dissection course for procedural training of anesthesiology residents. The course utilized "freedom art" embalmed human bodies that allowed trainees to perform ultrasound-based regional and neuraxial techniques followed by detailed dissections of critical anatomy. One hundred and four residents participated in workshops and small group discussions and were evaluated using pre- and post-course assessments. A variety of clinical techniques were performed on the bodies, including regional blocks and neuraxial catheter placement. Insertion of peripheral/neuraxial catheters was successful, with dissections demonstrating the expected placement. Assessment scores improved following the course (pre-course mean 52.7%, standard deviation (σ) 13.1%; post-course mean 72.2%, σ 11.6%; t-test p < 0.0001) and feedback highlighted the usefulness and clinical relevance of course content. The ability to correlate ultrasound imaging with subsequent dissections of the "blocked" area and visualization of dye staining was extremely relevant for spatial understanding of the anatomy relevant for the clinical practice of these techniques. This manuscript demonstrates successful implementation of a comprehensive course for anesthesiology resident physicians to address gaps in undergraduate anatomical education and suggests that broader adoption of dissection courses may be beneficial for training anesthesiologists.

Analgesic options for anterior approach to scoliosis repair: a scoping review.

PURPOSE: The ideal analgesic regimen for the anterior approach to scoliosis repair is not clearly defined. The purpose of the study was to summarize and identify gaps in the current literature specific to the anterior approach to scoliosis repair. METHODS: A scoping review was conducted in July 2022 utilizing PubMed, Cochrane, and Scopus databases guided by the PRISMA-ScR framework. RESULTS: The database search generated 641 possible articles, 13 of which met all inclusion criteria. All articles focused on the effectiveness and safety of regional anesthetic techniques, while a minority also provided both opioid and non-opioid medication frameworks. CONCLUSION: Continuous Epidural Analgesia (CEA) is the most well-studied intervention for pain control in anterior scoliosis repair, but other, more novel regional anesthetic techniques offer safe and effective potential alternatives. More research is indicated to compare the effectiveness of different regional techniques and perioperative medication regimens specific to anterior scoliosis repair.

Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Managing COVID-19 from the epicenter: adaptations and suggestions based on experience.

In March 2020, the New York City metropolitan area became the epicenter of the United States' SARS-CoV-2 pandemic and the surge of new cases threatened to overwhelm the area's hospital systems. This article describes how an anesthesiology department at a large urban academic hospital rapidly adapted and deployed to meet the threat head-on. Topics included are preparatory efforts, development of a team-based staffing model, and a new strategy for resource management. While still maintaining a fully functioning operating theater, discrete teams were deployed to both COVID-19 and non-COVID-19 intensive care units, rapid response/airway management team, the difficult airway response team, and labor and delivery. Additional topics include the creation of a temporary 'pop-up' anesthesiology-run COVID-19 intensive care unit utilizing anesthesia machines for monitoring and ventilatory support as well as the development of a simulation and innovation team that was instrumental in the rapid prototyping of a controlled split-ventilation system and conversion of readily available BIPAP units into emergency ventilators. As the course of the disease is uncertain, the goal of this article is to assist others in preparation for what may come next with COVID-19 as well as potential future pandemics.

Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor.

Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp3-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL. A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program.

Discovery of N-Ethyl-4-[2-(4-fluoro-2,6-dimethyl-phenoxy)-5-(1-hydroxy-1-methyl-ethyl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (ABBV-744), a BET Bromodomain Inhibitor with Selectivity for the Second Bromodomain.

The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (>70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (∼40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound 27 demonstrating greater than 100-fold selectivity for BRD4 BD2 over BRD4 BD1. Further optimization to improve BD2 selectivity and oral bioavailability resulted in the clinical development compound 46 (ABBV-744).

Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.

Optimizing cerebral oxygenation in cardiac surgery: A randomized controlled trial examining neurocognitive and perioperative outcomes.

OBJECTIVE: The study objective was to determine whether targeted therapy to optimize cerebral oxygenation is associated with improved neurocognitive and perioperative outcomes. METHODS: In a prospective trial, intraoperative cerebral oximetry monitoring using bilateral forehead probes was performed in cardiac surgical patients who were randomly assigned to an intervention group in which episodes of cerebral oxygen desaturation (<60% for >60 consecutive seconds at either probe) triggered an intervention protocol or a control group in which the cerebral oximetry data were hidden from the clinical team, and no intervention protocol was applied. Cognitive testing was performed preoperatively and at postoperative months 3 and 6; domains studied were response speed, processing speed, attention, and memory. Perioperative outcomes studied were death, hospital length of stay, intensive care unit length of stay, postoperative day of extubation, time on mechanical ventilation, intensive care unit delirium, Sequential Organ Failure Assessment on intensive care unit admission, and intensive care unit blood transfusion. RESULTS: Group mean memory change scores were significantly better in the intervention group at 6 months (0.60 [standard error, 0.30] vs -0.17 [standard error, 0.33], adjusted P = .008). However, presence, duration, and severity of cerebral desaturation were not associated with cognitive change scores. Perioperative outcomes did not differ between the intervention and control groups. CONCLUSIONS: Targeted therapy to optimize cerebral oxygenation was associated with better memory outcome in a group of cardiac surgical patients. Some aspects of the protocol other than desaturation duration and severity contributed to the observed neuroprotective effect.

Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors.

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.

Simulated death enhances learner attitudes regarding simulation.

Introduction: Despite the widespread use of simulated death in healthcare education, some view it as a controversial learning tool due to potential psychological harm. Others believe that allowing death during simulation enhances participant learning. Sparse data exist in the literature about learner attitudes towards simulated death. Our objective was to establish a link between exposure to simulated death and learner attitudes regarding simulation. Our hypothesis was that exposure to simulated death will positively affect learner attitudes towards simulation. Methods: Anonymous surveys were distributed to participants of simulations conducted by our department from January 2014 to December 2015. Collected survey data included total number of simulation scenarios, exposure to death and participants' views towards simulation afterwards. Participants also rated the simulation on a Likert scale. We compared demographic and simulation data for participants who experienced simulated death versus participants who did not. Exposure to death and clinical level were included as predictor variables in logistic regressions using the simulator experience variables as outcomes. Results: 250 survey responses were analysed. 64% of participants were attendings. 82% of participants experienced death during simulation. The group that experienced simulated death gave significantly higher ratings (4.77 vs 4.50, p=0.004) and a higher percentage of maximum ratings on the Likert scale (83% vs 59%, p=0.0002). More participants who experienced death thought that simulated death could enhance learning (76% vs 59%, p=0.021). When adjusted for training level, those who experienced death in simulation were nearly twice as likely to think that death can enhance learning (p=0.049) and 133% more likely to give the simulation the highest rating (p=0.036). Conclusions: Survey participants who experienced simulated death were more likely to think that death can enhance learning and more likely to give the simulation the highest rating, thereby demonstrating that exposure to simulated death positively affects learner attitudes regarding simulation.

Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor.

The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9-19-fold. Additional structure-activity relationship (SAR) efforts aimed both at increasing potency and improving pharmacokinetic properties led to the discovery of the clinical candidate 63 (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation.

Potential mechanisms of resistance to venetoclax and strategies to circumvent it.

BACKGROUND: Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges. METHODS: In order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines. RESULTS: Gene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti-apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro-apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax-binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance. CONCLUSIONS: Overall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance.

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors.

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 µM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.

Methylpyrrole inhibitors of BET bromodomains.

An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.

Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.

A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.

Effect of radiotherapy planning complexity on survival of elderly patients with unresected localized lung cancer.

PURPOSE: To evaluate whether complex radiotherapy (RT) planning was associated with improved outcomes in a cohort of elderly patients with unresected Stage I-II non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Using the Surveillance, Epidemiology, and End Results registry linked to Medicare claims, we identified 1998 patients aged >65 years with histologically confirmed, unresected stage I-II NSCLC. Patients were classified into an intermediate or complex RT planning group using Medicare physician codes. To address potential selection bias, we used propensity score modeling. Survival of patients who received intermediate and complex simulation was compared using Cox regression models adjusting for propensity scores and in a stratified and matched analysis according to propensity scores. RESULTS: Overall, 25% of patients received complex RT planning. Complex RT planning was associated with better overall (hazard ratio 0.84; 95% confidence interval, 0.75-0.95) and lung cancer-specific (hazard ratio 0.81; 95% confidence interval, 0.71-0.93) survival after controlling for propensity scores. Similarly, stratified and matched analyses showed better overall and lung cancer-specific survival of patients treated with complex RT planning. CONCLUSIONS: The use of complex RT planning is associated with improved survival among elderly patients with unresected Stage I-II NSCLC. These findings should be validated in prospective randomized controlled trials.