Evaluating Diagnostic Algorithms for Heparin-Induced Thrombocytopenia using Two Combined Automated Rapid Immunoassays.

Heparin-induced thrombocytopenia (HIT) is an autoimmune disorder caused by antibodies against platelet factor 4 (PF4) and heparin complexes. Rapid immunoassays (IAs) for detection of these antibodies mark a milestone in HIT diagnosis, despite a higher false-positive rate compared with functional platelet-activation assays. However, combining different rapid IAs may help to improve their diagnostic specificity. Here, we compared the individual performance of the latex immunoturbidimetric assay (LIA; HemosIL HIT-Ab [PF4-H]; sensitivity 91.7%, specificity 68.4%) and chemiluminescence immunoassay (CLIA; HemosIL AcuStarHIT-Ab [PF4-H]; sensitivity 92.4%, specificity 85.8%) with their combined performance using two unique diagnostic algorithms in a single prospective cohort of suspected HIT patients. Using the simultaneous algorithm adapted from Warkentin et al, the combined LIA-CLIA had a sensitivity of 99.0% and specificity of 64.3%. The sequential algorithm adapted from Rittener-Ruff et al was applied in two theoretical scenarios to reflect real-world circumstances in diagnostic laboratories where access to clinical information is limited: (1) assuming all patients had an intermediate 4Ts score and (2) assuming all patients had a high 4Ts score. This algorithm correctly predicted HIT in 94.5% (high 4Ts) and 96.0% (intermediate 4Ts) and excluded HIT in 82.6% (high 4Ts) and 80.1% (intermediate 4Ts) of patients in either scenario, respectively. Although both combined algorithms improved diagnostic performance of individual IAs, the simultaneous algorithm showed fewer false predictions (7.9%) than the sequential algorithm (intermediate 4Ts: 37.6% and high 4Ts: 41.5%) and proved more practical as it does not rely on physician evaluations. Our findings highlight the importance of accounting for clinician and interlaboratory variability when evaluating diagnostic tests for HIT.

Working viscosity and non-Newtonian behavior of silicone denture liners.

PURPOSE: To evaluate flow profile and non-Newtonian behavior of 10 different silicone lining materials. METHODS: Ten commercially available silicone lining materials were selected for evaluation. The flow profile and non-Newtonian behavior of each material was measured using a shark fin testing method. Fin height and resultant base thickness were measured with a digital caliper and compared with one-way ANOVA and Student-Newman-Keuls post hoc test and fin base by Kruskal-Wallis one-way ANOVA on ranks with Dunn post hoc test with significance at P< 0.05 for both. RESULTS: Shark fin heights ranged from 9.62 ± 0.86 mm [Reline II (Soft)] to 25.54 ± 0.43 mm [Sofreliner (Medium)]. Shark fin bases ranged from 2.57 ± 0.51 mm [Sofreliner (Medium)] to 10.31 ± 0.57 mm [Reline II (Soft)]. Statistically significant differences were found between certain samples' shark fin heights as well as resultant bases (P< 0.05) indicating different rheological properties. CLINICAL SIGNIFICANCE: Silicone liner materials differ significantly with respect to flow profile and non-Newtonian behavior. While a high flow profile (low viscosity) of an elastomeric impression material improves accuracy, it may be a detriment to a denture lining material that must achieve a critical minimum thickness to provide resilience. Likewise, a low flow profile (high viscosity) material may also pose a disadvantage, requiring excessive compression and possible tissue distortion to achieve the same critical thickness. The results of this study should be considered when selecting the appropriate material for clinical application. Additional studies are indicated to further quantify rheological properties as well as correlate them to physical properties after the complete cure of the material.

Nature-Based Solution to Eliminate Cyanotoxins in Water Using Biologically Enhanced Biochar.

Climate change and high eutrophication levels of freshwater sources are increasing the occurrence and intensity of toxic cyanobacterial blooms in drinking water supplies. Conventional water treatment struggles to eliminate cyanobacteria/cyanotoxins, and expensive tertiary treatments are needed. To address this, we have designed a sustainable, nature-based solution using biochar derived from waste coconut shells. This biochar provides a low-cost porous support for immobilizing microbial communities, forming biologically enhanced biochar (BEB). Highly toxic microcystin-LR (MC-LR) was used to influence microbial colonization of the biochar by the natural lake-water microbiome. Over 11 months, BEBs were exposed to microcystins, cyanobacterial extracts, and live cyanobacterial cells, always resulting in rapid elimination of toxins and even a 1.6-1.9 log reduction in cyanobacterial cell numbers. After 48 h of incubation with our BEBs, the MC-LR concentrations dropped below the detection limit of 0.1 ng/mL. The accelerated degradation of cyanotoxins was attributed to enhanced species diversity and microcystin-degrading microbes colonizing the biochar. To ensure scalability, we evaluated BEBs produced through batch-scale and continuous-scale pyrolysis, while also guaranteeing safety by maintaining toxic impurities in biochar within acceptable limits and monitoring degradation byproducts. This study serves as a proof-of-concept for a sustainable, scalable, and safe nature-based solution for combating toxic algal blooms.

Post-cardiac surgery thrombotic thrombocytopenic purpura: presence of anti-ADAMTS13 autoantibodies at preoperative baseline.

Thrombotic thrombocytopenic purpura (TTP) rarely complicates acute inflammatory conditions such as surgery, including post-cardiac surgery. Review of 32 previously-reported cases of post-cardiac surgery TTP indicates that this disorder often occurs as early as 2-3 days following surgery, which seems too soon to implicate new formation of anti-ADAMTS13 autoantibodies as a consequence of surgery itself. We diagnosed post-cardiac surgery TTP in a 60-year-old female that began approximately 3 days post-coronary artery bypass surgery in which anti-ADAMTS13 autoantibodies were implicated. We therefore investigated whether anti-ADAMTS13 autoantibodies were also present in a preoperative blood sample. Inhibitory (neutralizing) anti-ADAMTS13 autoantibodies were detectable in the preoperative blood sample, suggesting that the role of surgery in precipitating TTP might be due to effects such as abrupt increase in postoperative von Willebrand factor levels and associated proinflammatory factors, rather than effects of surgery itself leading to the formation of de novo anti-ADAMTS13 autoantibodies.

Serotonin-release assay-positive but platelet factor 4-dependent enzyme-immunoassay negative: HIT or not HIT?

IgG-specific and polyspecific PF4-dependent enzyme-immunoassays (EIAs) have exceptionally high sensitivity (≥99%) for diagnosis of heparin-induced thrombocytopenia (HIT), a drug reaction caused by platelet-activating antibodies detectable by serotonin-release assay (SRA). The IgG-specific EIAs are recommended for screening, as their high sensitivity is accompanied by relatively high specificity vis-à-vis polyspecific EIAs. We investigated the frequency of SRA-positive/EIA-negative (SRA+/EIA-) HIT, prompted by referral to our reference HIT laboratory of serial blood samples from a patient ("index case") with false-negative IgG-specific EIAs. Despite initial clinical suspicion for HIT, repeat negative IgG-specific EIAs prompted heparin resumption, which triggered recurrent thrombocytopenia and near-fatal cardiac arrest, indicating likely post-heparin HIT-associated anaphylactoid reaction. Further investigations revealed a strong-positive SRA, whether performed with heparin alone, PF4 alone, or PF4/heparin, with inhibition by Fc receptor-blocking monoclonal antibody (indicating IgG-mediated platelet activation); however, five different IgG-specific immunoassays yielded primarily negative (or weak-positive) results. To investigate the frequency of SRA+/EIA- HIT, we reviewed the laboratory and clinical features of patients with this serological profile during a 6-year period in which our reference laboratory investigated for HIT using both SRA and IgG-specific EIA. Although ~0.2% of 8546 patients had an SRA+/EIA- profile, further review of 15 such cases indicated clerical/laboratory misclassification or false-positive SRA in all, with no SRA+/EIA- HIT case identified. We conclude that while SRA+/EIA- HIT is possible-as shown by our index case-this clinical picture is exceptionally uncommon. Moreover, the requirement for a positive EIA is a useful quality control maneuver that reduces risk of reporting a false-positive SRA result.

Collaboration among nurses when transitioning older adults between hospital and community settings: a scoping review.

BACKGROUND: The transitioning of older patients between healthcare sectors requires the provision of high-quality nursing care. Collaboration among nurses is identified as an essential element of transitional care, yet nurse-nurse collaboration has received little attention. AIM: The aim of this study was to examine the extent, range and nature of nurse-nurse collaboration when transitioning older patients between hospital and community settings, and to identify gaps in the literature. METHODS: Arksey and O'Malley's (International Journal of Social Research Methodology, 8, 2005 and 19) framework was used to undertake a scoping review to answer the research questions: how do nurses collaborate together when transitioning older patients from hospital to community settings and what are the facilitators, barriers and outcomes of nurse-nurse collaboration when transitioning older patients between sectors? The Nurse-Nurse Collaboration Scale (NNCS) subdomains informed the identification of selected studies. RESULTS: Twelve papers were included with most coming from Scandinavian countries and the majority using qualitative methodologies. Communication, coordination and professionalism were found to be both facilitators and barriers of nurse-nurse collaboration. Gaps in the literature included conflict management, and the outcomes of collaboration which was only reported in one study. CONCLUSIONS: The findings indicate there is limited study of collaboration among nurses when transitioning older patients between hospital and community settings. Future research should address the impact of conflict on nurses working in collaborative practice as well as conducting intervention studies to examine the outcomes of nurse-nurse collaboration.

Autoantibodies to thrombopoietin and the thrombopoietin receptor in patients with immune thrombocytopenia.

Autoantibodies to thrombopoietin (TPO, also termed THPO) or the TPO receptor (cMpl, also termed MPL) could play a pathological role in immune thrombocytopenia (ITP). In this study, we tested for autoantibodies against TPO, cMpl, or the TPO/cMpl complex in ITP and other thrombocytopenic disorders. Using an inhibition step with excess TPO in fluid-phase to improve binding specificity, the prevalence of anti-TPO autoantibodies was: active ITP: 9/32 (28%); remission ITP: 0/14 (0%); non-immune thrombocytopenias: 1/10 (10%); and healthy controls: 1/11 (9%). Similarly, using an inhibition step with excess cMpl, the prevalence of specific anti-cMpl autoantibodies was: active ITP: 7/32 (22%); remission ITP: 1/14 (7%); non-immune thrombocytopenias: 3/10 (30%); and healthy controls: 0/11 (0%). Two active ITP patients had autoantibodies against the TPO/cMpl complex, but not against TPO or cMpl alone. Anti-TPO or anti-cMpl autoantibodies were found in 44% of ITP patients, and in 40% of patients with other thrombocytopenic disorders. These autoantibodies did not correlate with ITP disease severity or number of ITP treatments received; however, in this cohort, 3 patients failed to respond to TPO receptor agonist medications, and of those, 2 had anti-TPO autoantibodies. This suggests that anti-TPO and anti-cMpl autoantibodies are associated with thrombocytopenia, and may be clinically relevant in a subset of ITP patients.

Development of a high-yield expression and purification system for platelet factor 4.

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction characterized by IgG antibodies bound to complexes of platelet factor 4 (PF4) and heparin. The majority of diagnostic tests for HIT rely on an exogenous source of PF4 to identify anti-PF4/heparin antibodies. These include the PF4-dependent enhanced serotonin release assay (PF4-SRA) among others. Using a bacterial expression system, we developed a novel and efficient method of producing recombinant human PF4 (rhPF4) that is biochemically and antigenically similar to platelet-derived human PF4. rhPF4 was produced using the pET expression system in the BL21(DE3) strain of Escherichia coli. The system was optimized for protein expression using isopropyl ß-D-1-thiogalactopyranoside at different induction temperatures and incubation times. rhPF4 solubility was improved by using different detergents during cell lysis and by purifying with heparin affinity and ion exchange chromatography. Biochemical characteristics of rhPF4 were investigated using mass spectrometry, SDS-PAGE analysis, and gel filtration chromatography and compared to platelet-derived PF4. Antigenic and functional characteristics of rhPF4 were studied using the anti-PF4/heparin EIA and the PF4-SRA. Using this method, we could produce 11.4 ± 0.6 mg of pure rhPF4 per liter of bacterial culture. Absorbance readings from the anti-PF4/heparin EIA using platelet-derived and rhPF4 were highly correlated (n = 194; r = 0.9545, p < 0.0001); and functional release of serotonin in the PF4-SRA induced by anti-PF4/heparin antibodies was similar to either platelet-derived or rhPF4 and heparin (r = 0.9597, p < 0.0001). Our method of rhPF4 production is efficient and does not rely on a source of platelets. The rhPF4 purification method described produces greater yields at a lower cost than other current methods. The application of this method can improve the efficiency of biochemical investigations and HIT diagnostic testing by supplying sufficient amounts of PF4.

Optimizing insulin delivery for patients with diabetes.

Management of diabetes for residents in long-term care settings is particularly challenging, due to the wide range of physical and mental limitations that bear on efficacy of their medications, as well as practical issues associated with the optimal administration of these medications. Foremost among the practical issues for residents requiring insulin injections, is the need to ensure that it is consistently delivered to the circulation at the target rate and dosage, thereby avoiding life-threatening episodes of hypoglycemia. Recent evidence from a multinational survey has elucidated principles of insulin injection technique, including optimal needle length and site rotation that can greatly improve consistency in delivering insulin to the subcutaneous compartment, while reducing pain, improving patient compliance, and limiting the total daily dosage. The present review consolidates these findings and highlights the most critical take-home messages for healthcare professionals working in this area.

The body of knowledge in thanatology: An outline.

The Association for Death Education and Counseling has updated its articulation of the body of knowledge in the field of thanatology. In doing so it has relinquished the use of a matrix format in favor of a more serviceable outline containing three major sections: Arenas of Thanatology, Practice Considerations for Professionals in the Field, and Contextual and Theoretical Considerations. Accompanying the outline is a new commentary on the state of the field itself, along with an annotated bibliography of recent relevant publications.

Phosphatidylserine externalization and procoagulant activation of erythrocytes induced by Pseudomonas aeruginosa virulence factor pyocyanin.

The opportunistic pathogen Pseudomonas aeruginosa causes a wide range of infections in multiple hosts by releasing an arsenal of virulence factors such as pyocyanin. Despite numerous reports on the pleiotropic cellular targets of pyocyanin toxicity in vivo, its impact on erythrocytes remains elusive. Erythrocytes undergo an apoptosis-like cell death called eryptosis which is characterized by cell shrinkage and phosphatidylserine (PS) externalization; this process confers a procoagulant phenotype on erythrocytes as well as fosters their phagocytosis and subsequent clearance from the circulation. Herein, we demonstrate that P. aeruginosa pyocyanin-elicited PS exposure and cell shrinkage in erythrocyte while preserving the membrane integrity. Mechanistically, exposure of erythrocytes to pyocyanin showed increased cytosolic Ca(2+) activity as well as Ca(2+) -dependent proteolytic processing of µ-calpain. Pyocyanin further up-regulated erythrocyte ceramide abundance and triggered the production of reactive oxygen species. Pyocyanin-induced increased PS externalization in erythrocytes translated into enhanced prothrombin activation and fibrin generation in plasma. As judged by carboxyfluorescein succinimidyl-ester labelling, pyocyanin-treated erythrocytes were cleared faster from the murine circulation as compared to untreated erythrocytes. Furthermore, erythrocytes incubated in plasma from patients with P. aeruginosa sepsis showed increased PS exposure as compared to erythrocytes incubated in plasma from healthy donors. In conclusion, the present study discloses the eryptosis-inducing effect of the virulence factor pyocyanin, thereby shedding light on a potentially important mechanism in the systemic complications of P. aeruginosa infection.

Producing megakaryocytes from a human peripheral blood source.

BACKGROUND: Cultured megakaryocytes could prove useful in the study of human diseases, but it is difficult to produce sufficient numbers for study. We describe and evaluate the use of an expansion process to develop mature megakaryocytes from peripheral blood-derived human hematopoietic stem and progenitor cells (HSPCs). STUDY DESIGN AND METHODS: HSPCs (CD34+) were isolated from peripheral blood by positive selection and expanded using an optimal CD34+ expansion supplement. We evaluated megakaryocyte growth, maturation, and morphology in response to thrombopoietin (TPO) stimulation using flow cytometry and electron microscopy. TPO demonstrated a dose-dependent stimulatory effect on both megakaryocyte number and maturation. RESULTS: From 90 to 120 mL of unmanipulated peripheral blood, we isolated a mean of 1.5 × 10(5) HSPCs (1.5 × 10(3) cells/mL of whole blood). HSPCs expanded nine-fold after a 4-day culture using an expansion supplement. Expanded cells were cultured for an additional 8 days with TPO (20 ng/mL), which resulted in a 2.9-fold increase in megakaryocytic cells where 83% of live cells expressed CD41a+, a marker of megakaryocyte commitment, and 50% expressed CD42b+, a marker for megakaryocyte maturation. The expanded HSPCs responded to TPO stimulation to yield more than 1.0 × 10(6) megakaryocytes. This cell number was sufficient for morphologic studies that demonstrated these expanded HSPCs produced mature polyploid megakaryocytes capable of forming proplatelet extensions. CONCLUSIONS: Peripheral blood HSPCs can be expanded and differentiated into functional, mature megakaryocytes, a finding that supports the use of this process to study inherent platelet (PLT) production disorders as well as study factors that impair normal PLT production.

Does hearing the patient perspective improve consultation skills in examinations? An exploratory randomized controlled trial in medical undergraduate education.

PURPOSE: Medical education increasingly includes patient perspectives, but few studies look at the impact on students' proficiency in standard examinations. We explored students' exam performance after viewing video of patients' experiences. METHODS: Eighty-eight medical students were randomized to one of two e-learning modules. The experimental group saw video clips of patients describing their colposcopy, while the control group viewed a clinician describing the procedure. Students then completed a Multiple Choice Questionnaire (MCQ) and were assessed by a blinded clinical examiner in an Objective Structured Clinical Examination (OSCE) with a blinded simulated patient (SP). The SP scored students using the Doctors' Interpersonal Skills Questionnaire (DISQ). Students rated the module's effect on their skills and confidence. Regression analyses were used to compare the effect of the two modules on these outcomes, adjusting for gender and graduate entry. RESULTS: The experimental group performed better in the OSCE than the control group (odds ratio 2.7 [95%CI 1.2-6.1]; p = 0.016). They also reported significantly more confidence in key areas, including comfort with patients' emotions (odds ratio 6.4 [95%CI 2.7-14.9]; p < 0.0005). There were no other significant differences. CONCLUSION: Teaching that included recorded elements of real patient experience significantly improved students' examination performance and confidence.

Pitfalls in the diagnosis of heparin-Induced thrombocytopenia: A 6-year experience from a reference laboratory.

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies against complexes of platelet factor 4 (PF4) and heparin. The diagnosis of HIT is contingent on accurate and timely laboratory testing. Recently, alternative anticoagulants for the treatment of HIT have been introduced along with algorithms for better HIT diagnosis. However, the increased reliance on immunoassays for the diagnosis of HIT may have harmful consequences due to the high rate of false positive results. To compare trends and implications of current HIT testing approaches, we analyzed results over a six-year period from the McMaster University Platelet Immunology Reference Laboratory. From 2008 to 2013, 8,546 samples were investigated for HIT using both an in-house IgG-specific anti-PF4/heparin enzyme immunoassay (EIA) and the serotonin-release assay (SRA). Of 8,546 samples tested, 13.4% were true-positives (positive in both assays); 65.6% were true-negatives (negative in both assays); 20.9% were presumed false positive for HIT (EIA-positive/SRA-negative); and 0.2% were EIA-negative/SRA-positive. The frequency of EIA-positive/SRA-negative results increased over time (from 12.9% in 2008 to 22.9% in 2013). We found that the number of SRA-negative samples was reduced from referring centers that used an immunoassay as an initial screen; however, 41% of those samples tested negative in the immunoassay and in the SRA at the reference laboratory. The suspicion of HIT continues at a high rate and the agreement between the EIA and SRA test results remains problematic.

Synthesis of 4-Arylthieno[2,3-b]pyridines and 4-Aminothieno[2,3-b]pyridines via a Regioselective Bromination of Thieno[2,3-b]pyridine.

The first regioselective, mild bromination of thieno[2,3-b]pyridine is described herein. The reaction proceeds with selectivity toward the 4-position (87% isolated yield). Subsequent cross-coupling reactions proceed in excellent yields and demonstrate the potential of 4-bromothieno[2,3-b]pyridine as a building block for use in drug discovery research.

Deficiency of the ferrous iron transporter FeoAB is linked with metronidazole resistance in Bacteroides fragilis.

BACKGROUND: Metronidazole is the most commonly used antimicrobial for Bacteroides fragilis infections and is recommended for prophylaxis of colorectal surgery. Metronidazole resistance is increasing and the mechanisms of resistance are not clear. METHODS: A transposon mutant library was generated in B. fragilis 638R (BF638R) to identify the genetic loci associated with resistance to metronidazole. RESULTS: Thirty-two independently isolated metronidazole-resistant mutants had a transposon insertion in BF638R_1421 that encodes the ferrous transport fusion protein (feoAB). Deletion of feoAB resulted in a 10-fold increased MIC of metronidazole for the strain. The metronidazole MIC for the feoAB mutant was similar to that for the parent strain when grown on media supplemented with excess iron, suggesting that the increase seen in the MIC of metronidazole was due to reduced cellular iron transport in the feoAB mutant. The furA gene repressed feoAB transcription in an iron-dependent manner and disruption of furA resulted in constitutive transcription of feoAB, regardless of whether or not iron was present. However, disruption of feoAB also diminished the capacity of BF638R to grow in a mouse intraperitoneal abscess model, suggesting that inorganic ferrous iron assimilation is essential for B. fragilis survival in vivo. CONCLUSIONS: Selection for feoAB mutations as a result of metronidazole treatment will disable the pathogenic potential of B. fragilis and could contribute to the clinical efficacy of metronidazole. While mutations in feoAB are probably not a direct cause of clinical resistance, this study provides a key insight into intracellular metronidazole activity and the link with intracellular iron homeostasis.

Relational ethics in everyday practice.

Oncology nurses frequently encounter ethical issues in their everyday practice because of the complex needs of patients, which require the expertise of many health care providers. The involvement of various health care providers, as well as of the patient and family means there is the potential for differing views about what is best for the patient. The focus of this paper is to share a case history describing the ethical issues experienced by nurses and to illustrate how relational ethics can offer guidance for nurses caring for patients with cancer.

Effect of buttonhole cannulation with a polycarbonate PEG on in-center hemodialysis fistula outcomes: a randomized controlled trial.

BACKGROUND: Quality improvement strategies to increase and maintain the numbers of arteriovenous fistulas (AVFs) are a critical drive in enhancing the quality of care of patients receiving treatment with hemodialysis. How the AVF is needled is an important consideration in AVF survival; the ideal cannulation technique has not been established to date. STUDY DESIGN: Prospective randomized single-center trial. SETTING & PARTICIPANTS: Patients on maintenance hemodialysis therapy (N = 140). INTERVENTION: A 1-year intervention of buttonhole (constant site) or usual-practice (different site) cannulation. OUTCOMES: Primary study outcome was AVF survival over 1 year, in which AVF failure was defined as an AVF no longer used for hemodialysis (also referred to as assisted patency). Secondary outcomes included primary patency, number of access interventions, bleeding time, infection rate, cannulation time and pain, and aneurysm formation. RESULTS: Demographic data were similar for both groups. The primary outcome measure of AVF survival at 1 year was statistically significantly increased in the buttonhole group (100% vs 86% with usual practice; P = 0.005, log-rank test). In the buttonhole group, there were fewer interventions (19% vs 39% in usual practice) and less existing aneurysm enlargement (23% vs 67% in usual practice). There were no bacteremia events in the buttonhole group and 2 in the usual-practice group (0.09/1,000 AVF days). There were no significant differences in bleeding times and lignocaine use between the 2 groups. LIMITATIONS: A single-center study, lack of blinding. CONCLUSIONS: In this study, AVF survival was significantly greater when using buttonhole cannulation. The buttonhole technique significantly decreased the need for access interventions and reduced existing aneurysm enlargement. Concerns of increased infection rates or prolonged bleeding times with the buttonhole technique were not seen in this study. The buttonhole technique should be considered the cannulation technique of choice for AVFs.

Trineopentylphosphine: a conformationally flexible ligand for the coupling of sterically demanding substrates in the Buchwald-Hartwig amination and Suzuki-Miyaura reaction.

Trineopentylphosphine (TNpP) in combination with palladium provides a highly effective catalyst for the Buchwald-Hartwig coupling of sterically demanding aryl bromides and chlorides with sterically hindered aniline derivatives. Excellent yields are obtained even when both substrates include 2,6-diisopropyl substituents. Notably, the reaction rate is inversely related to the steric demand of the substrates. X-ray crystallographic structures of Pd(TNpP)2, [Pd(4-t-Bu-C6H4)(TNpP)(µ-Br)]2, and [Pd(2-Me-C6H4)(TNpP)(µ-Br)]2 are reported. These structures suggest that the conformational flexibility of the TNpP ligand plays a key role in allowing the catalyst to couple hindered substrates. The Pd/TNpP system also shows good activity for the Suzuki coupling of hindered aryl bromides.

Stereospecific Suzuki, Sonogashira, and Negishi coupling reactions of N-alkoxyimidoyl iodides and bromides.

A high-yielding stereospecific route to the synthesis of single geometric isomers of diaryl oxime ethers through Suzuki coupling of N-alkoxyimidoyl iodides is described. This reaction occurs with complete retention of the imidoyl halide geometry to give single E- or Z-isomers of diaryl oxime ethers. The Sonogashira coupling of N-alkoxyimidoyl iodides and bromides with a wide variety of terminal alkynes to afford single geometric isomers of aryl alkynyl oxime ethers has also been developed. Several of these reactions proceed through copper-free conditions. The Negishi coupling of N-alkoxyimidoyl halides is introduced. The E and Z configurations of nine Suzuki-coupling products and two Sonogashira-coupling products were confirmed by X-ray crystallography.