Roles for cerebellum and subsumption architecture in central pattern generation.

Within vertebrates, central pattern generators drive rhythmical behaviours, such as locomotion and ventilation. Their pattern generation is also influenced by sensory input and various forms of neuromodulation. These capabilities arose early in vertebrate evolution, preceding the evolution of the cerebellum in jawed vertebrates. This later evolution of the cerebellum is suggestive of subsumption architecture that adds functionality to a pre-existing network. From a central-pattern-generator perspective, what additional functionality might the cerebellum provide? The suggestion is that the adaptive filter capabilities of the cerebellum may be able to use error learning to appropriately repurpose pattern output. Examples may include head and eye stabilization during locomotion, song learning, and context-dependent alternation between learnt motor-control sequences.

Oxidative Cross Dehydrogenative Coupling of N-Heterocycles with Aldehydes through C(sp3)-H Functionalization.

Existing methodologies for metal-catalyzed cross-couplings typically rely on preinstallation of reactive functional groups on both reaction partners. In contrast, C-H functionalization approaches offer promise in simplification of the requisite substrates; however, challenges from low reactivity and similar reactivity of various C-H bonds introduce considerable complexity. Herein, the oxidative cross dehydrogenative coupling of α-amino C(sp3)-H bonds and aldehydes to produce ketone derivatives is described using an unusual reaction medium that incorporates the simultaneous use of di-tert-butyl peroxide as an oxidant and zinc metal as a reductant. The method proceeds with a broad substrate scope, representing an attractive approach for accessing α-amino ketones through the formal acylation of C-H bonds α to nitrogen in N-heterocycles. A combination of experimental investigation and computational modeling provides evidence for a mechanistic pathway involving cross-selective nickel-mediated cross-coupling of α-amino radicals and acyl radicals.

Comparison of acoustic particle acceleration detection capabilities in three shark species.

Behavioural studies have shown that sharks are capable of directional orientation to sound. However, only one previous experiment addresses the physiological mechanisms of directional hearing in sharks. Here, we used a directional shaker table in combination with the auditory evoked potential (AEP) technique to understand the broadscale directional hearing capabilities in the New Zealand carpet shark (Cephaloscyllium isabellum), rig shark (Mustelus lenticulatus) and school shark (Galeorhinus galeus). The aim of this experiment was to test if sharks are more sensitive to vertical (z-axis) or head-to-tail (x-axis) accelerations, and whether there are any differences between species. Our results support previous findings, suggesting that shark ears can receive sounds from all directions. Acceleration detection bandwidth was narrowest for the carpet shark (40-200 Hz), and broader for rig and school sharks (40-800 Hz). Greatest sensitivity bands were 40-80 Hz for the carpet shark, 100-200 Hz for the rig and 80-100 Hz for the school shark. Our results indicate that there may be differences in directional hearing abilities among sharks. The bottom-dwelling carpet shark was equally sensitive to vertical and head-to-tail particle accelerations. In contrast, both benthopelagic rig and school sharks appeared to be more sensitive to vertical accelerations at frequencies up to 200 Hz. This is the first study to provide physiological evidence that sharks may differ in their directional hearing and sound localisation abilities. Further comparative physiological and behavioural studies in more species with different lifestyles, habitats and feeding strategies are needed to further explore the drivers for increased sensitivity to vertical accelerations among elasmobranchs.

Comparison of auditory evoked potential thresholds in three shark species.

Auditory sensitivity measurements have been published for only 12 of the more than 1150 extant species of elasmobranchs (sharks, skates and rays). Thus, there is a need to further understand sound perception in more species from different ecological niches. In this study, the auditory evoked potential (AEP) technique was used to compare hearing abilities of the bottom-dwelling New Zealand carpet shark (Cephaloscyllium isabellum) and two benthopelagic houndsharks (Triakidae), the rig (Mustelus lenticulatus) and the school shark (Galeorhinus galeus). AEPs were measured in response to tone bursts (frequencies: 80, 100, 150, 200, 300, 450, 600, 800 and 1200 Hz) from an underwater speaker positioned 55 cm in front of the shark in an experimental tank. AEP detection thresholds were derived visually and statistically, with statistical measures slightly more sensitive (∼4 dB) than visual methodology. Hearing abilities differed between species, mainly with respect to bandwidth rather than sensitivity. Hearing was least developed in the benthic C. isabellum [upper limit: 300 Hz, highest sensitivity: 100 Hz (82.3±1.5 dB re. 1 µm s-2)] and had a wider range in the benthopelagic rig and school sharks [upper limit: 800 Hz; highest sensitivity: 100 Hz (79.2±1.6 dB re. 1 µm s-2) for G. galeus and 150 Hz (74.8±1.8 dB re. 1 µm s-2) for M. lenticulatus]. The data are consistent with those known for 'hearing non-specialist' teleost fishes that detect only particle motion, not pressure. Furthermore, our results provide evidence that benthopelagic sharks exploit higher frequencies (max. 800 Hz) than some of the bottom-dwelling sharks (max. 300 Hz). Further behavioural and morphological studies are needed to identify what ecological factors drive differences in upper frequency limits of hearing in elasmobranchs.

Tolerability and Efficacy of a 10:25 Preparation of Δ9-Tetrahydrocannabinol and Cannabidiol for Treatment of Chronic Back or Neck Pain: A Multiple-Dose Escalation Study.

Introduction: The aim was to demonstrate the safety and tolerability of cannabidiol (CBD) with Δ9-THC in patients with moderate to severe chronic back or neck pain unresponsive to over-the-counter non-opioid analgesics. Methods: This was a non-randomized, single-arm, open-label study. Participants received escalating doses of an oromucosal-administered combination containing 10 mg/mL of Δ9-THC, 25 mg/mL of CBD. On day 1, patients received once-daily 0.5 mL Cybis® 10:25 (5 mg Δ9-THC plus 12.5 mg CBD daily), escalated at days 8, 15, and 22 to 0.5 mL twice-daily (bd) (10 mg Δ9-THC plus 25 mg CBD daily), 1.0 mL bd (20 mg Δ9-THC plus 50 mg CBD daily), and 1.5 mL bd (30 mg Δ9-THC plus 75 mg CBD daily), respectively. The primary outcome was safety and tolerability, with secondary objectives including pharmacokinetic and efficacy outcomes. Results: 28 patients were enrolled in the study. Their median age was 63.3 years, and half were female. The median history of neck/back pain was 10 years. The pharmacokinetics following single doses of 0.5 mL were variable; however, there were dose-dependent increases in trough levels of CBD and Δ9-THC. Cybis® 10:25 was well tolerated, with the majority of adverse events of mild severity. The most common adverse events were nausea, vomiting, fatigue, dizziness, headache, paresthesia, and anxiety. There were dose-dependent improvements in numerical pain rating scores (p < 0.001), with clinically significant reductions in pain at 1.0 mL bd and 1.5 mL bd doses (28.8% and 34.1% reductions, respectively, p < 0.001). Depressive symptoms and stress had dose-dependent reductions (p = 0.0182, p < 0.01, respectively). Conclusion: In patients with chronic neck/back pain, CBD and Δ9-THC are well tolerated and doses of 1.0 mL bd and 1.5 mL bd showed clinically significant reductions in pain compared to baseline pain scores.

Fish bioacoustics: Navigating underwater sound.

Fish bioacoustics is about the sounds produced by fish, how fish hear, and what they hear. The focus of this article is on the hypothesis that some late pelagic stage reef fish larvae use the marine soundscape to locate reef settlement habitat. The hypothesis is evaluated by consideration of the nature of reef sound, hearing ability in late-stage larval fish, and direct behavioral evidence for orientation to reef sound.

Operant conditioning as a tool to assess hearing abilities in sharks.

Sharks (elasmobranchs) are an ancient, diverse group of fishes, representing a basal stage in the evolution of vertebrate hearing. Yet, our understanding of behavioural measures of hearing abilities in sharks is limited. To address this, an operant conditioning paradigm was designed, and scalloped hammerhead Sphyrna lewini and rig (spotted estuary smooth hound) Mustelus lenticulatus were successfully trained to respond to pure-tone acoustic stimuli from an underwater speaker. After 2-3 weeks of training, both species showed distinctive responses to these acoustic stimuli and retained this behaviour when reinforced. S. lewini responded to a 400 Hz pulsed tone with an abrupt increase in tailbeat frequency (97 beats per 30 s vs. 69 beats for a 2 kHz control and 70 beats for no signal) and sustained vigorous swimming (arousal response) for at least 30 s. In response to a 200 Hz pulsed tone, M. lenticulatus visited a target area under the speaker significantly more frequently (13.4 ± 4.3 times per minute vs. 1.4 ± 1.5 times for a 1.2 kHz control and 0.9 ± 0.01 times for no signal) and swam circles under the speaker to search for food. The authors used S. lewini arousal responses to pure-tone stimuli of 40, 80, 200, 400, 600 and 800 Hz to generate a provisional hearing-threshold curve. The results show that S. lewini adapts to low-frequency hearing (greatest sensitivity at 200 Hz, upper limit 800 Hz), which is like other coastal pelagic sharks that have been investigated so far. Despite challenges operant acoustic conditioning studies are a viable method for revealing auditory capabilities of sharks.

Machine learning based assessment of small-bodied fish tracking to evaluate spoiler baffle fish passage design.

Fish passage research is important to mitigate the adverse effects of fragmented river habitats caused by waterway structures. The scale at which this research is undertaken varies from small-scale laboratory prototype studies to in-situ observations at various fish passage structures and bottlenecks. Using DeepLabCut, we introduce and evaluate a machine learning based workflow to track small-bodied fish in order to facilitate improved fish passage management. We specifically studied the behaviour and kinematics of Galaxias maculatus, a widespread diadromous Southern Hemisphere fish species. Upstream fish passage was studied in the presence of three different patches of spoiler baffles at an average water velocity of 0.4 m/s. In semi-supervised mode, the fish locations were extracted, and fish behaviour, such as swimming pathways and resting locations, was analysed based on extracted positions and recorded kinematic parameters. Individual fish behaviour and kinematic parameters were then used to assess the suitability of the three different spoiler baffle designs for enhancing fish passage. Using this technique, we were able to demonstrate where different spoiler baffle configurations resulted in significant differences in fish passage success and behaviour. For example, medium-spaced smaller baffles provided more accessible and uniform resting locations, which were required for efficient upstream passage. Results are discussed in relation to fish passage management at small instream structures.

Investigations into mechanism and origin of regioselectivity in the metallaphotoredox-catalyzed α-arylation of N-alkylbenzamides.

A mechanistic study on the α-arylation of N-alkylbenzamides catalyzed by a dual nickel/photoredox system using aryl bromides is reported herein. This study elucidates the origins of site-selectivity of the transformation, which is controlled by the generation of a hydrogen atom transfer (HAT) agent by a photocatalyst and bromide ions in solution. Tetrabutylammonium bromide was identified as a crucial additive and source of a potent HAT agent, which led to increases in yields and a lowering of the stoichiometries of the aryl bromide coupling partner. NMR titration experiments and Stern-Volmer quenching studies provide evidence for complexation to and oxidation of bromide by the photocatalyst, while elementary steps involving deprotonation of the N-alkylbenzamide or 1,5-HAT were ruled out through mechanistic probes and kinetic isotope effect analysis. This study serves as a valuable tool to better understand the α-arylation of N-alkylbenzamides, and has broader implications in halide-mediated C-H functionalization reactions.

Nickel-Catalyzed Defluorinative Coupling of Aliphatic Aldehydes with Trifluoromethyl Alkenes.

A simple procedure is reported for the nickel-catalyzed defluorinative alkylation of unactivated aliphatic aldehydes. The process involves the catalytic reductive union of trifluoromethyl alkenes with aldehydes using a nickel complex of a 6,6'-disubstituted bipyridine ligand with zinc metal as the terminal reductant. The protocol is distinguished by its broad substrate scope, mild conditions, and simple catalytic setup. Reaction outcomes are consistent with the intermediacy of an α-silyloxy(alkyl)nickel intermediate generated by a low-valent nickel catalyst, silyl electrophile, and the aldehyde substrate. Mechanistic findings with cyclopropanecarboxaldehyde provide insights into nature of the reactive intermediates and illustrate fundamental reactivity differences that are governed by subtle changes in ligand and substrate structure.

Application of power analysis to determine the optimal reporting time frame for use in statewide trauma system quality reporting.

BACKGROUND: Meaningful reporting of quality metrics relies on detecting a statistical difference when a true difference in performance exists. Larger cohorts and longer time frames can produce higher rates of statistical differences. However, older data are less relevant when attempting to enact change in the clinical setting. The selection of time frames must reflect a balance between being too small (type II errors) and too long (stale data). We explored the use of power analysis to optimize time frame selection for trauma quality reporting. METHODS: Using data from 22 Level III trauma centers, we tested for differences in 4 outcomes within 4 cohorts of patients. With bootstrapping, we calculated the power for rejecting the null hypothesis that no difference exists amongst the centers for different time frames. From the entire sample for each site, we simulated randomly generated datasets. Each simulated dataset was tested for whether a difference was observed from the average. Power was calculated as the percentage of simulated datasets where a difference was observed. This process was repeated for each outcome. RESULTS: The power calculations for the 4 cohorts revealed that the optimal time frame for Level III trauma centers to assess whether a single site's outcomes are different from the overall average was 2 years based on an 80% cutoff. CONCLUSION: Power analysis with simulated datasets allows testing of different time frames to assess outcome differences. This type of analysis allows selection of an optimal time frame for benchmarking of Level III trauma center data.

Glycosyl Exchange of Unactivated Glycosidic Bonds: Suppressing or Embracing Side Reactivity in Catalytic Glycosylations.

While developing boron-catalyzed glycosylations using glycosyl fluoride donors and trialkylsilyl ether acceptors, competing pathways involving productive glycosylation or glycosyl exchange were observed. Experimental and computational mechanistic studies suggest a novel mode of reactivity where a dioxolenium ion is a key intermediate that promotes both pathways through addition to either a silyl ether or to the acetal of an existing glycosidic linkage. Modifications in catalyst structure enable either pathway to be favored, and with this understanding, improved multicomponent iterative couplings and glycosyl exchange processes were demonstrated.

Graft Survival and Segment Discards Among Split-Liver and Reduced-Size Transplantations in the United States From 2008 to 2018.

Split-liver transplantation has allocation advantages over reduced-size transplantation because of its ability to benefit 2 recipients. However, prioritization of split-liver transplantation relies on the following 3 major assumptions that have never been tested in the United States: similar long-term transplant recipient outcomes, lower incidence of segment discard among split-liver procurements, and discard of segments among reduced-size procurements that would be otherwise "transplantable." We used United Network for Organ Sharing Standard Transplant Analysis and Research data to identify all split-liver (n = 1831) and reduced-size (n = 578) transplantation episodes in the United States between 2008 and 2018. Multivariable Cox proportional hazards modeling was used to compare 7-year all-cause graft loss between cohorts. Secondary analyses included etiology of 30-day all-cause graft loss events as well as the incidence and anatomy of discarded segments. We found no difference in 7-year all-cause graft loss (adjusted hazard ratio [aHR], 1.1; 95% confidence interval [CI], 0.8-1.5) or 30-day all-cause graft loss (aHR, 1.1; 95% CI, 0.7-1.8) between split-liver and reduced-size cohorts. Vascular thrombosis was the most common etiology of 30-day all-cause graft loss for both cohorts (56.4% versus 61.8% of 30-day graft losses; P = 0.85). Finally, reduced-size transplantation was associated with a significantly higher incidence of segment discard (50.0% versus 8.7%) that were overwhelmingly right-sided liver segments (93.6% versus 30.3%). Our results support the prioritization of split-liver over reduced-size transplantation whenever technically feasible.

Activation Mechanism of Nickel(0) N-Heterocyclic Carbene Catalysts Stabilized by Fumarate Ligands.

Nickel(0) catalysts of N-heterocyclic carbenes (NHCs) that are stabilized by electron-deficient alkenes possess desirable properties of air tolerance and ease of handling while also retaining high catalytic activities. Since catalyst stability often comes at the expense of catalytic activity, we have undertaken a detailed study of the activation mechanism of an IMes-nickel(0) catalyst stabilized by di(o-tolyl) fumarate that converts the stable precatalyst form into a catalytically active species. Computational evaluation provided evidence against a simple ligand exchange as the activation mechanism for this catalyst, and a stoichiometric activation process that covalently modifies the stabilizing ligand was identified. A detailed computational picture for the activation process was developed, with predictive insights that elucidate an unexpected catalyst activation pathway that operates when ligand exchange is thermodynamically unfavorable.

Sources of Postacute Care Episode Payment Variation After Traumatic Hip Fracture Repair Among Medicare Beneficiaries: Cross-Sectional Retrospective Study.

The objective of this study was to evaluate how much variation in postacute care (PAC) spending after traumatic hip fracture exists between hospitals, and to what degree this variation is explained by patient factors, hospital factors, PAC setting, and PAC intensity. Background: Traumatic hip fracture is a common and costly event. This is particularly relevant given our aging population and that a substantial proportion of these patients are discharged to PAC settings. Methods: It is a cross-sectional retrospective study. In a retrospective review using Medicare claims data between 2014 and 2019, we identified PAC payments within 90 days of hospitalization discharges and grouped hospitals into quintiles of PAC spending. The degree of variation present in PAC spending across hospital quintiles was evaluated after accounting for patient case-mix factors and hospital characteristics using multivariable regression models, adjusting for PAC setting choice by fixing the proportion of PAC discharge disposition across hospital quintiles, and adjusting for PAC intensity by fixing the amount of PAC spending across hospital quintiles. The study pool included 125,745 Medicare beneficiaries who underwent operative management for traumatic hip fracture in 2078 hospitals. The primary outcome was PAC spending within 90 days of discharge following hospitalization for traumatic hip fracture. Results: Mean PAC spending varied widely between top versus bottom spending hospital quintiles ($31,831 vs $17,681). After price standardization, the difference between top versus bottom spending hospital quintiles was $8,964. Variation between hospitals decreased substantially after adjustment for PAC setting ($25,392 vs $21,274) or for PAC intensity ($25,082 vs $21,292) with little variation explained by patient or hospital factors. Conclusions: There was significant variation in PAC payments after a traumatic hip fracture between the highest- and lowest-spending hospital quintiles. Most of this variation was explained by choice of PAC discharge setting and intensity of PAC spending, not patient or hospital characteristics. These findings suggest potential systems-level inefficiencies that can be targeted for intervention to improve the appropriateness and value of healthcare spending.

Video is better: why aren't we using it? A mixed-methods study of the barriers to routine procedural video recording and case review.

INTRODUCTION: Video-based case review for minimally invasive surgery is immensely valuable for education and quality improvement. Video review can improve technical performance, shorten the learning curve, disseminate new procedures, and improve learner satisfaction. Despite these advantages, it is underutilized in many institutions. So far, research has focused on the benefits of video, and there is relatively little information on barriers to routine utilization. METHODS: A 36-question survey was developed on video-based case review and distributed to the SAGES email list. The survey included closed and open-ended questions. Numeric responses and Likert scales were compared with t-test; open-ended responses were reviewed qualitatively through rapid thematic analysis to identify themes and sub-themes. RESULTS: 642 people responded to the survey for a response rate of 11%. 584 (91%) thought video would improve the quality of educational conferences. 435 qualitative responses on the value of video were analyzed, and benefits included (1) improved understanding, (2) increased objectivity, (3) better teaching, and (4) better audience engagement. Qualitative comments regarding specific barriers to recording and editing case video identified challenges at all stages of the process, from (1) the decision to record a case, (2) starting the recording in the OR, (3) transferring and storing files, and (4) editing the file. Each step had its own specific challenges. CONCLUSION: Minimally invasive surgeons want to increase their utilization of video-based case review, but there are multiple practical challenges to overcome. Understanding these barriers is essential in order to increase use of video for education and quality improvement.

Reliability of hospital-level mortality in abdominal aortic aneurysm repair.

OBJECTIVE: The relationship between volume and surgical outcomes has been shown for a variety of surgical procedures. The effects in abdominal aortic aneurysm repair have continued to be debated. Reliability adjustment has been used as a method to remove statistical noise from hospital-level outcomes. However, its impact on aortic aneurysm repair is not well understood. METHODS: We used prospectively collected data from the Vascular Quality Initiative to identify all patients who had undergone abdominal aortic aneurysm repair from 2003 to 2019. We first calculated the hospital-level risk-adjusted 30-day mortality rates. We subsequently used hierarchical logistic regression modeling to adjust for measurement reliability using empirical Bayes techniques. The effect of volume on risk- and reliability-adjusted mortality rates was then assessed using linear regression. RESULTS: Between 2003 and 2019, 67,073 abdominal aortic aneurysms were repaired, of which 11,601 (17.3%) were repaired with an open approach. The median annual volume was 7.4 (interquartile range, 3.0-13.3) for open repairs and 35.4 (interquartile range, 18.8-59.8) for endovascular repairs. Of the 223 hospitals that had performed open repairs during the study period, only 11 (4.9%) had performed ≥15 open repairs annually, and the risk-adjusted mortality rates varied from 0% to 75% across all centers. After reliability adjustment, the variability of the risk-adjusted mortality rates had decreased significantly to 1.3% to 8.2%. The endovascular repair risk-adjusted mortality rate variability had decreased from 0% to 14.3% to 0.3% to 2.8% after reliability adjustment. A decreasing trend in mortality was found with increasing an annual case volume for open repair with each additional annual case associated with a 0.012% decrease in mortality (P = .05); however, the relationship was not significant for endovascular repair (P = .793). CONCLUSIONS: We found that most hospitals do not perform a sufficient number of annual cases to generate a reliable center-specific mortality rate for open aneurysm repair. Center-specific mortality rates for low-volume centers should be viewed with caution, because a substantial proportion of the variation for these outcomes will be statistical noise rather than true center-level differences in the quality of care.

Nickel-Catalyzed Decarboxylative Coupling of Redox-Active Esters with Aliphatic Aldehydes.

The addition of alkyl fragments to aliphatic aldehydes is a highly desirable transformation for fragment couplings, yet existing methods come with operational challenges related to the basicity and instability of the nucleophilic reagents commonly employed. We report herein that nickel catalysis using a readily available bioxazoline (BiOx) ligand can catalyze the reductive coupling of redox-active esters with aliphatic aldehydes using zinc metal as the reducing agent to deliver silyl-protected secondary alcohols. This protocol is operationally simple, proceeds under mild conditions, and tolerates a variety of functional groups. Initial mechanistic studies suggest a radical chain pathway. Additionally, alkyl tosylates and epoxides are suitable alkyl precursors to this transformation providing a versatile suite of catalytic reactions for the functionalization of aliphatic aldehydes.

Population-based Trends in Obesity and Kidney Transplantation Among Patients With End-stage Kidney Disease.

Obesity is a barrier to transplant, reducing access and leading to worse outcomes versus nonobese adults. Most transplant centers in the United States maintain body mass index (BMI) cutoffs to listing for kidney transplantation of 35 to 40 kg/m2. There is little contemporary data on the prevalence of obesity among patients with end-stage kidney disease (ESKD) despite its impact on clinical outcomes and healthcare expenditures. METHODS: We utilized data from the US Renal Data System from 2008 to 2016 to identify a prevalent cohort of 1 079 410 patients with ESKD. Linear regression determined trends in the proportion of patients within each category of BMI. We also evaluated geographic variation in rates of obesity and transplantation across the United States. RESULTS: Among the 1 079 410 ESKD patients, the largest cohort of patients were those with obesity (n = 423 270; 39.2%). There were 309 707 (28.7%) patients with an overweight BMI and 274 683 (25.4%) with a normal BMI. The proportion of patients with obesity increased significantly from 36.8% in 2008 to 40.2% in 2016 (trend 0.28; 95% confidence interval, 0.05-0.51). There was significant geographic variation by state with rates of obesity ranging from 32.3% to 45.4% and state transplant rates among those obese patients ranging from 22.5% to 46.8%. There is a weak correlation between states with increased rates of obese ESKD patients and states with an increased obesity transplant rate as indicated with r = 0.40 (P = 0.003). CONCLUSIONS: Beneficiaries with obesity are now the largest and fastest growing demographic among patients with ESKD in the United States.

Nickel-catalyzed reductive coupling of unactivated alkyl bromides and aliphatic aldehydes.

A mild, convenient coupling of aliphatic aldehydes and unactivated alkyl bromides has been developed. The catalytic system features the use of a common Ni(ii) precatalyst and a readily available bioxazoline ligand and affords silyl-protected secondary alcohols. The reaction is operationally simple, utilizing Mn as a stoichiometric reductant, and tolerates a wide range of functional groups. The use of 1,5-hexadiene as an additive is an important reaction parameter that provides significant benefits in yield optimizations. Initial mechanistic experiments support a mechanism featuring an alpha-silyloxy Ni species that undergoes formal oxidative addition to the alkyl bromide via a reductive cross-coupling pathway.