Phosphorus-mediated sp2-sp3 couplings for C-H fluoroalkylation of azines.

Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence almost all metrics associated with their pharmacokinetic and pharmacodynamic profile1-4. Drug candidates increasingly contain trifluoromethyl (CF3) and difluoromethyl (CF2H) groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect and plant life5,6. New fluoroalkylation reactions have undoubtedly stimulated this shift; however, methods that directly convert C-H bonds into C-CF2X groups (where X is F or H) in complex drug-like molecules are rare7-13. Pyridines are the most common aromatic heterocycles in pharmaceuticals14, but only one approach-via fluoroalkyl radicals-is viable for achieving pyridyl C-H fluoroalkylation in the elaborate structures encountered during drug development15-17. Here we develop a set of bench-stable fluoroalkylphosphines that directly convert the C-H bonds in pyridine building blocks, drug-like fragments and pharmaceuticals into fluoroalkyl derivatives. No preinstalled functional groups or directing groups are required. The reaction tolerates a variety of sterically and electronically distinct pyridines, and is exclusively selective for the 4-position in most cases. The reaction proceeds through initial formation of phosphonium salts followed by sp2-sp3 coupling of phosphorus ligands-an underdeveloped manifold for forming C-C bonds.

Synthesis of 15N-Pyridines and Higher Mass Isotopologs via Zincke Imine Intermediates.

Methods to incorporate stable radioisotopes are integral to pharmaceutical and agrochemical development. However, despite the prevalence of pyridines in candidate compounds, methods to incorporate 15N atoms within their structures are limited. Here, we present a general approach to pyridine 15N-labeling that proceeds via ring-opening to NTf-Zincke imines and then ring-closure with commercially available 15NH4Cl salts. This process functions on a range of substituted pyridines, from simple building block-type compounds to late-stage labeling of complex pharmaceuticals, and 15N-incorporation is >95% in most cases. The reactivity of the Zincke imine intermediates also enables deuteration of the pyridine C3- and C5-positions, resulting in higher mass isotopologs required for LCMS analysis of biological fluids during drug development.

Expert Consensus Recommendations for Robotic Surgery Credentialing.

OBJECTIVE: To define criteria for robotic credentialing using expert consensus. BACKGROUND: A recent review of institutional robotic credentialing policies identified significant variability and determined current policies are largely inadequate to ensure surgeon proficiency and may threaten patient safety. METHODS: Twenty-eight national robotic surgery experts were invited to participate in a consensus conference. After review of available institutional policies and discussion, the group developed a 91 proposed criteria. Using a modified Delphi process the experts were asked to indicate their agreement with the proposed criteria in three electronic survey rounds after the conference. Criteria that achieved 80% or more in agreement (consensus) in all rounds were included in the final list. RESULTS: All experts agreed that there is a need for standardized robotic surgery credentialing criteria across institutions that promote surgeon proficiency. Forty-nine items reached consensus in the first round, 19 in the second, and 8 in the third for a total of 76 final items. Experts agreed that privileges should be granted based on video review of surgical performance and attainment of clearly defined objective proficiency benchmarks. Parameters for ongoing outcome monitoring were determined and recommendations for technical skills training, proctoring, and performance assessment were defined. CONCLUSIONS: Using a systematic approach, detailed credentialing criteria for robotic surgery were defined. implementation of these criteria uniformly across institutions will promote proficiency of robotic surgeons and has the potential to positively impact patient outcomes.

Are current credentialing requirements for robotic surgery adequate to ensure surgeon proficiency?

BACKGROUND: Robotic surgery has seen unprecedented growth, requiring hospitals to establish or update credentialing policies regarding this technology. Concerns about verification of robotic surgeon proficiency and the adequacy of current credentialing criteria to maintain patient safety have arisen. The aim of this project was to examine existing institutional credentialing requirements for robotic surgery and evaluate their adequacy in ensuring surgeon proficiency. METHODS: Robotic credentialing policies for community and academic surgery programs were acquired and reviewed. Common criteria across institutions related to credentialing and recredentialing were identified and the average, standard deviation, and range of numeric requirements, if defined, was calculated. Criteria for proctors and assistants were also analyzed. RESULTS: Policies from 42 geographically dispersed US hospitals were reviewed. The majority of policies relied on a defined number of proctored cases as a surrogate for proficiency with an average of 3.24 ± 1.69 and a range of 1-10 cases required for initial credentialing. While 34 policies (81%) addressed maintenance of privileges requirements, there was wide variability in the average number of required robotic cases (7.19 ± 3.28 per year) and range (1-15 cases per year). Only 11 policies (26%) addressed the maximum allowable time gap between robotic cases. CONCLUSION: Significant variability in credentialing policies exists in a representative sample of US hospitals. Most policies require completion of a robotic surgery training course and a small number of proctored cases; however, ongoing objective performance assessments and patient outcome monitoring was rarely described. Existing credentialing policies are likely inadequate to ensure surgeon proficiency; therefore, development and wide implementation of robust credentialing guidelines is recommended to optimize patient safety and outcomes.

Selective Halogenation of Pyridines Using Designed Phosphine Reagents.

Halopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C-H precursors are lacking. We designed a set of heterocyclic phosphines that are installed at the 4-position of pyridines as phosphonium salts and then displaced with halide nucleophiles. A broad range of unactivated pyridines can be halogenated, and the method is viable for late-stage halogenation of complex pharmaceuticals. Computational studies indicate that C-halogen bond formation occurs via an SNAr pathway, and phosphine elimination is the rate-determining step. Steric interactions during C-P bond cleavage account for differences in reactivity between 2- and 3-substituted pyridines.

Proving the Effectiveness of the Fundamentals of Robotic Surgery (FRS) Skills Curriculum: A Single-blinded, Multispecialty, Multi-institutional Randomized Control Trial.

OBJECTIVE: To demonstrate the noninferiority of the fundamentals of robotic surgery (FRS) skills curriculum over current training paradigms and identify an ideal training platform. SUMMARY BACKGROUND DATA: There is currently no validated, uniformly accepted curriculum for training in robotic surgery skills. METHODS: Single-blinded parallel-group randomized trial at 12 international American College of Surgeons (ACS) Accredited Education Institutes (AEI). Thirty-three robotic surgery experts and 123 inexperienced surgical trainees were enrolled between April 2015 and November 2016. Benchmarks (proficiency levels) on the 7 FRS Dome tasks were established based on expert performance. Participants were then randomly assigned to 4 training groups: Dome (n = 29), dV-Trainer (n = 30), and DVSS (n = 32) that trained to benchmarks and control (n = 32) that trained using locally available robotic skills curricula. The primary outcome was participant performance after training based on task errors and duration on 5 basic robotic tasks (knot tying, continuous suturing, cutting, dissection, and vessel coagulation) using an avian tissue model (transfer-test). Secondary outcomes included cognitive test scores, GEARS ratings, and robot familiarity checklist scores. RESULTS: All groups demonstrated significant performance improvement after skills training (P < 0.01). Participating residents and fellows performed tasks faster (DOME and DVSS groups) and with fewer errors than controls (DOME group; P < 0.01). Inter-rater reliability was high for the checklist scores (0.82-0.97) but moderate for GEARS ratings (0.40-0.67). CONCLUSIONS: We provide evidence of effectiveness for the FRS curriculum by demonstrating better performance of those trained following FRS compared with controls on a transfer test. We therefore argue for its implementation across training programs before surgeons apply these skills clinically.

Potential impact of strong tobacco-control policies in 11 newly independent states.

OBJECTIVE: While some countries of the WHO European Region are global leaders in tobacco control, the Newly Independent States (NIS) have the highest tobacco-smoking prevalence globally and a relatively low overall level of the WHO Framework Convention on Tobacco Control (WHO FCTC) implementation. An abridged version of the SimSmoke tobacco control policy simulation model has been developed to project the health impact of implementing tobacco-control policies in line with the WHO FCTC. METHODS: Data on population size, smoking prevalence, policy-specific effect sizes and formulas were applied in 11 NIS - Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, the Russian Federation, Tajikistan, Turkmenistan, Ukraine, and Uzbekistan. The aim was to project the relative reduction in smoking prevalence, number of smokers and number of smoking-attributable deaths resulting from implementing six individual and/or combined WHO FCTC measures. RESULTS: An increase in excise cigarette taxes to 75% of price yields the largest relative reduction in smoking prevalence (range 12.1-44%) for all countries. The projections show that when all six tobacco control measures are fully implemented in line with the WHO FCTC, smoking prevalence in each of the NIS countries can be reduced by at least 39% by the year 2033 (baseline 2015). CONCLUSION: The projections show that the NIS countries can expect a large number of smoking-attributable deaths just among those smokers alive today, but large reductions in smoking prevalence and smoking-attributable deaths can be achieved if the WHO FCTC demand reduction policies are implemented. The results can be used as an advocacy tool for accelerating enforcement of tobacco control laws in NIS.

Potential health impact of strong tobacco control policies in 11 South Eastern WHO European Region countries.

Background: While some WHO European Region countries are global tobacco control leaders, the South Eastern region of Europe has the highest tobacco smoking prevalence globally and a relatively low level of overall implementation of the WHO Framework Convention on Tobacco Control (WHO FCTC). An abridged version of SimSmoke has been developed to project the health impact of implementing tobacco control policies in line with the WHO FCTC. Methods: Data on population size, smoking prevalence, policy-specific effect sizes and formulas were applied in 11 South Eastern WHO European Region countries [Albania, Bosnia and Herzegovina (the Federation of Bosnia and Herzegovina and the Republika Srpska), Bulgaria, Croatia, Israel, Montenegro, Republic of Moldova, Romania, Serbia, Slovenia and the former Yugoslav Republic of Macedonia] to project the relative reduction in smoking prevalence, number of smokers and number of smoking-attributable deaths resulting from implementing individual and/or combined six WHO FCTC measures. Results: For all countries, an increase in excise cigarette taxes to 75% of price yields the largest relative reduction in smoking prevalence (range 8-28%). The projections show that within 15 years smoking prevalence can be reduced by at least 30% in all countries when all six tobacco control measures are fully implemented in line with the WHO FCTC. Conclusion: The projections show that large health effects can be achieved and the results can be used as an advocacy tool towards acceleration of the enforcement of tobacco control laws in WHO European Region countries.

Travel distance: Impact on stage of presentation and treatment choices in head and neck cancer.

OBJECTIVES: The objective was to examine the impact of travel distance on stage of presentation and treatment choices in head and neck squamous cell carcinoma in the rural setting. METHODS: 6029 cases diagnosed from 2002 to 2011 were obtained from the state cancer registry. Travel time was calculated to the nearest academic medical centers, otolaryngologist, and radiation treatment facilities. Multivariate logistic regression was used to examine the association of travel time with stage of presentation as well as the likelihood of appropriate therapy after adjustment for other demographic variables. RESULTS: Patients in the highest quartile for travel distance to academic centers were 33% more likely to present with early stage disease (p = 0.02), and 42% more likely to receive appropriate surgical therapy for oral cavity cancer. Patients were 70% more likely to receive appropriate surgery if they were farthest from the nearest radiation center (p = 0.03). Proximity to otolaryngology care was not significant. CONCLUSION: Increased travel distance to academic medical centers is associated with increased likelihood of proper therapy for surgically treated tumors of the head and neck. Impact on these findings on improvements in access to care is discussed.

Application of the Abridged SimSmoke model to four Eastern Mediterranean countries.

INTRODUCTION: The WHO established the MPOWER policy package to boost the implementation of the WHO Framework Convention for Tobacco Control (WHO FCTC) in 2008 and to provide practical guidance on policies effective at reducing smoking rates. An easily applied Abridged SimSmoke was developed to help countries gauge the effect of these policies using data from the WHO MPOWER/WHO Report (MPOWER Report) and is applied to four Eastern Mediterranean countries. METHODS: The number of smokers in a country is calculated using the country's smoking prevalence and population. Policy effect sizes, based on previously validated SimSmoke models, are applied to the smoker populations to determine the reduction in the number of smokers resulting from implementing policies. The number of smoking-attributable deaths is derived based on findings that half of those smokers alive today will die from smoking. RESULTS: Within 40 years, implementing the complete set of MPOWER policies is projected to reduce smoking prevalence by 29% (range 15%, 41%) and avert almost 1 (range 0.5, 1.4) million deaths in Egypt, reduce smoking prevalence by 52% (range 36%, 66%) and avert 156 000 (106 000, 196 000) deaths in Lebanon, reduce smoking prevalence by 56% (range 40%, 69%) and avert 3.5 (range 2.5, 4.3) million deaths in Pakistan, and reduce smoking prevalence by 37% (range 21%, 51%) and avert 245 000 (range 138 000, 334 000) deaths in Tunisia. CONCLUSIONS: The Abridged SimSmoke model has been used to show the number of deaths from smoking and how MPOWER policies can be used to reach the WHO non-communicable deaths voluntary target for cigarette use reduction in four countries.

Outcomes of long-arm casting versus double-sugar-tong splinting of acute pediatric distal forearm fractures.

INTRODUCTION: The traditional treatment after closed reduction of distal radius (DR) and distal both bone (DBB) forearm fractures has been application of a long-arm cast (LAC) or a short-arm cast (SAC). Splinting is another option that avoids the potential complications associated with casting. The purpose of this study is to evaluate the maintenance of reduction of DR or DBB fractures placed in a double-sugar-tong splint (DSTS) compared with a LAC in a pediatric population. METHODS: This is an IRB-approved, prospective, randomized trial. Patients aged 4 to 12 years with DR or DBB fractures treated at a single institution between 2010 and 2012 were enrolled. After reduction, fractures were placed into either a LAC or a DSTS. Radiographs were reviewed at initial injury, postreduction, and at set intervals for angulation, displacement, and apposition, as well as cast index and 3-point index. The DSTS was overwrapped into a cast after week 1. The immobilization device was changed to a SAC at week 4 or 6. Total duration of immobilization was 6 to 8 weeks. RESULTS: Seventy-one patients were enrolled with 37 in the LAC and 34 in the DSTS. Average age was 8.73 years (range, 4 to 12) with 43 being males. There were 28 isolated DR and 43 DBB fractures. There were no week-to-week differences between the 2 groups in regards to sagittal alignment, coronal alignment, apposition, or displacement. Sagittal alignment at immediate postreduction and week 2 showed that the DSTS was slightly better (average 2.0 vs. 5.0 degrees, respectively, P=0.04). For the entire treatment period there was an increased risk of loss of reduction of ≥10 degrees in the LAC group versus the DSTS group (7 patients vs. 2 patients, respectively, P=0.0001), and of meeting the criteria for remanipulation (10 patients vs. 5 patients, respectively, P=0.01). At cast removal, there was no difference between groups. CONCLUSIONS: Although there were significant differences between the 2 groups with regards to risk of reduction loss, the DSTS and LAC were comparable in maintenance of reduction at the time of cast removal. Both the DSTS and LAC are appropriate immobilization devices for these pediatric fractures. LEVEL OF EVIDENCE: Level II-prospective, comparative study.

Evaluation of different approaches to define expert benchmark scores for new robotic training simulators based on the Medtronic HUGO™ RAS surgical robot experience.

New robot-assisted surgery platforms being developed will be required to have proficiency-based simulation training available. Scoring methodologies and performance feedback for trainees are currently not consistent across all robotic simulator platforms. Also, there are virtually no prior publications on how VR simulation passing benchmarks have been established. This paper compares methods evaluated to determine the proficiency-based scoring thresholds (a.k.a. benchmarks) for the new Medtronic Hugo™ RAS robotic simulator. Nine experienced robotic surgeons from multiple disciplines performed the 49 skills exercises 5 times each. The data were analyzed in 3 different ways: (1) include all data collected, (2) exclude first sessions, (3) exclude outliers. Eliminating the first session discounts becoming familiar with the exercise. Discounting outliers allows removal of potentially erroneous data that may be due to technical issues, unexpected distractions, etc. Outliers were identified using a common statistical technique involving the interquartile range of the data. Using each method above, mean and standard deviations were calculated, and the benchmark was set at a value of 1 standard deviation above the mean. In comparison to including all the data, when outliers are excluded, fewer data points are removed than just excluding first sessions, and the metric benchmarks are made more difficult by an average of 11%. When first sessions are excluded, the metric benchmarks are made easier by an average of about 2%. In comparison with benchmarks calculated using all data points, excluding outliers resulted in the biggest change making the benchmarks more challenging. We determined that this method provided the best representation of the data. These benchmarks should be validated with future clinical training studies.

Acute complications associated with removal of flexible intramedullary femoral rods placed for pediatric femoral shaft fractures.

BACKGROUND: The American Academy of Orthopaedic Surgeons position statement on the treatment of pediatric femoral shaft fractures could not comment on the safety of flexible intramedullary (IM) rod removal because of a lack of published evidence. This study reviews the acute complications of flexible IM rod removal from pediatric patients treated for femoral shaft fractures. METHODS: A retrospective clinical and radiographic analysis at a single institution over a 5-year period. Demographic and radiographic parameters were analyzed to determine their influence on intraoperative and immediate postoperative complications. RESULTS: One hundred sixty-three subjects (133 males, 30 females), mean age of 9.3±2.8 years (range, 2.7 to 14.8 y) and mean weight of 34.4±15.3 kg (range, 14.0 to 139.0 kg), underwent femoral flexible IM rod removal a mean 12.4±10.8 months (range, 2.4 to 63.8 mo) after placement with mean operative time of 51.1±22.3 minutes (range, 10 to 131 min). One hundred fifty-one subjects (92.6%) had stainless-steel Ender rods and the remaining nails were titanium. There were no significant demographic, intraoperative, or radiographic differences comparing subjects with Ender versus titanium rods. Indications for rod removal were pain at insertion site, family request, or surgeon's recommendation. There were 4 (2.5%) minor intraoperative difficulties, including the inability to remove 1 of 2 rods secondary to IM migration (n=1) and complete bone overgrowth at insertion site resulting in prolonged extraction time (n=3). Three of the 4 subjects had the rods placed >60 months before removal. Immediately postoperative (n=134), there were 4 (3.0%) complications, including superficial wound infection (n=3, 2.2%) and knee contracture (n=1, 0.8%). Subjects were released to full activities at a mean 4.7±1.8 weeks postoperatively with no known postoperative fractures. CONCLUSIONS: The rate of intraoperative and immediate postoperative complications is low. Neither patient demographics, fracture characteristics, nor operative technique influenced the complication rate. Intraoperative difficulties may be minimized with removal of rods before signs of overgrowth. LEVELS OF EVIDENCE: Level IV, intervention case series.

Treatment of Insertional Achilles Tendinosis With Polyurethane Urea-Based Matrix Augmentation.

INTRODUCTION: Surgical treatment for insertional Achilles tendinosis (IAT) sometimes requires tendon repair augmentation. The purpose of this study is to evaluate the efficacy of polycaprolactone-based polyurethane urea (PUUR) matrix augmentation in the treatment of IAT. METHODS: A retrospective review was performed in surgically treated IAT. Repairs were augmented with a PUUR matrix. Factors evaluated included date of full weightbearing, patient satisfaction, Visual Analog Scale (VAS) pain score, strength, and ankle motion. The Wilcoxon signed-rank test was used to compare baseline and final follow-up VAS scores. RESULTS: A total of 18 cases were included in the study. The mean patient age was 54.61 ± 8.25 (40-75) years with a mean follow-up of 163.61 ± 57.81 (92-314) days. Patient satisfaction was obtained on 15 of 18 patients, with 14 patients satisfied with their outcome. Mean VAS for pain significantly decreased from 6.19 ± 1.97 (2.5-9) to 0.83 ± 1.54 (0-5) postoperatively, which was statistically significant (P < .01). CONCLUSION: Achilles tendon augmentation with the PUUR matrix is a viable option in the treatment of IAT. Its use in this condition has minimal morbidity and can be an alternative to other forms of augmentation. LEVELS OF EVIDENCE: Level IV: Retrospective case series.

MIJ821 (onfasprodil) in healthy volunteers: First-in-human, randomized, placebo-controlled study (single ascending dose and repeated intravenous dose).

This single-center study administered MIJ821 (onfasprodil) as an intravenous infusion to healthy volunteers and included two parts: a single ascending dose study (Part 1) and a repeated intravenous dose study (Part 2). Primary objective was to evaluate the safety and tolerability of single ascending intravenous doses infused over a 40-min period and of two repeated doses (1 week apart) of MIJ821 in healthy volunteers. Secondary objectives were to assess the pharmacokinetics of MIJ821 after intravenous infusion in Part 1 and Part 2 of the study. Overall, 43 subjects in Part 1 and 12 subjects in Part 2 were randomized in the study. Median age in Part 1 and Part 2 was 45.0 and 43.5 years, respectively, with the majority being Caucasian (Part 1: 84%; Part 2: 92%). 19 subjects (44.2%) in Part 1 and 8 subjects (66.7%) in Part 2 experienced at least one adverse event (AE). Following single dose in Part 1 and Part 2, the AUCinf values of MIJ821 increased in a dose-proportional manner across the dose range 0.016-0.48 mg/kg and the Cmax values in a slight overproportional manner across the dose range 0.048-0.48 mg/kg. At the highest dose of 0.48 mg/kg, the geometric mean AUCinf was 708 h ng/mL and the geometric mean Cmax was 462 ng/mL. Inspection of 1-h post-dose resting electroencephalography activity across cohorts showed a relationship to administered dose, providing exploratory evidence of distal target engagement. In conclusion, MIJ821 showed a good safety and tolerability profile in healthy volunteers. Dissociative AEs were mild, transient, and dose-dependent.

SimSmokeFinn: how far can tobacco control policies move Finland toward tobacco-free 2040 goals?

AIMS: Finland is the first country to stipulate in law that its aim is to end the use of tobacco products containing compounds that are toxic to humans and that create addiction. This paper describes the development of a simulation model examining the potential effect of tobacco control policies in Finland on smoking prevalence and associated future premature mortality. METHODS: The model is developed using the SimSmoke simulation model of tobacco control policy, previously developed for other nations. The model uses population, smoking rates, and tobacco control policy data for Finland. It assesses, individually, and in combination, the effect of seven types of policies: taxes, smoke-free air laws, mass media campaigns, advertising bans, warning labels, cessation treatment, and youth access policies. RESULTS: With a comprehensive set of policies, smoking prevalence can be decreased by as much as 15% in the first few years, increasing to 29% by 20 years and 34% by 30 years. By 2040, 1300 deaths can be averted in that year alone with the stronger set of policies. Without effective tobacco control policies, 23,000 additional lives will be lost due to smoking over all years through 2040. CONCLUSIONS: The model shows that significant inroads to reducing smoking prevalence and premature mortality can be achieved through tax increases, a high-intensity media campaign complete with programmes to encourage cessation, a comprehensive cessation treatment programme, stronger health warnings, and enforcement of youth access laws. Other policies will be needed to further reduce tobacco use.

Geocoding precision of birth records from 2008 to 2017 in Kentucky, USA.

Maternal address information captured on birth records is increasingly used to estimate residential environmental exposures during pregnancy. However, there has been limited assessment of the geocoding precision of birth records, particularly since the adoption of the 2003 standard birth certificate in 2015. To address this gap, this study evaluated the geocoding precision of live and stillbirth records of Kentucky residents over ten years, from 2008 through 2017. This study summarized the demographic characteristics of imprecisely geocoded records and, using a bivariate logistic regression, identified covariates associated with poor geocoding precision among three population density designations-metro, non-metro, and rural. We found that in metro areas, after adjusting for area deprivation, education, and the race, age and education of both parents, records for Black mothers had 48% lower odds of imprecise geocoding (aOR=0.52, 95% CI: 0.48, 0.56), while Black women in rural areas had 96% higher odds of imprecise geocoding (aOr=1.96, 95% CI: 1.68, 2.28). This study also found that over the study period, rural and non-metro areas began with a high proportion of imprecisely geocoded records (38% in rural areas, 19% in non-metro), but both experienced an 8% decline in imprecisely geocoded records over the study period (aOr=0.92, 95% CI: 0.92, 0.94). This study shows that, while geocoding precision has improved in Kentucky, further work is needed to improve geocoding in rural areas and address racial and ethnic disparities.

Halogenation of the 3-position of pyridines through Zincke imine intermediates.

Pyridine halogenation reactions are crucial for obtaining the vast array of derivatives required for drug and agrochemical development. However, despite more than a century of synthetic endeavors, halogenation processes that selectively functionalize the carbon-hydrogen bond in the 3-position of a broad range of pyridine precursors remain largely elusive. We report a reaction sequence of pyridyl ring opening, halogenation, and ring closing whereby the acyclic Zincke imine intermediates undergo highly regioselective halogenation reactions under mild conditions. Experimental and computational mechanistic studies indicate that the nature of the halogen electrophile can modify the selectivity-determining step. Using this method, we produced a diverse set of 3-halopyridines and demonstrated late-stage halogenation of complex pharmaceuticals and agrochemicals.

Artificial Intelligence Methods and Artificial Intelligence-Enabled Metrics for Surgical Education: A Multidisciplinary Consensus.

BACKGROUND: Artificial intelligence (AI) methods and AI-enabled metrics hold tremendous potential to advance surgical education. Our objective was to generate consensus guidance on specific needs for AI methods and AI-enabled metrics for surgical education. STUDY DESIGN: The study included a systematic literature search, a virtual conference, and a 3-round Delphi survey of 40 representative multidisciplinary stakeholders with domain expertise selected through purposeful sampling. The accelerated Delphi process was completed within 10 days. The survey covered overall utility, anticipated future (10-year time horizon), and applications for surgical training, assessment, and feedback. Consensus was agreement among 80% or more respondents. We coded survey questions into 11 themes and descriptively analyzed the responses. RESULTS: The respondents included surgeons (40%), engineers (15%), affiliates of industry (27.5%), professional societies (7.5%), regulatory agencies (7.5%), and a lawyer (2.5%). The survey included 155 questions; consensus was achieved on 136 (87.7%). The panel listed 6 deliverables each for AI-enhanced learning curve analytics and surgical skill assessment. For feedback, the panel identified 10 priority deliverables spanning 2-year (n = 2), 5-year (n = 4), and 10-year (n = 4) timeframes. Within 2 years, the panel expects development of methods to recognize anatomy in images of the surgical field and to provide surgeons with performance feedback immediately after an operation. The panel also identified 5 essential that should be included in operative performance reports for surgeons. CONCLUSIONS: The Delphi panel consensus provides a specific, bold, and forward-looking roadmap for AI methods and AI-enabled metrics for surgical education.